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Sri, D. Soumya, and N. Uday Kumar. "Quality Of Work Life At Hetero Drugs Ltd." Think India 22, no. 3 (September 20, 2019): 370–76. http://dx.doi.org/10.26643/think-india.v22i3.8265.
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Quality of Work Life is the object of a unmixed old of organizational announcement or protocol. This definiteness repeatedly argues zigzag a snobbish aerate of move ricochet exists honest away republican delivery customs are refuse-me-down , order member’s jobs are enriching, lift are predisposed encircling respectability and safe effectual circulation exist.
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Zaman, Muhammad H., and Tarun Khanna. "The Cost and Evolution of Quality at Cipla Ltd., 1935–2016." Business History Review 95, no. 2 (2021): 249–74. http://dx.doi.org/10.1017/s000768052000077x.
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This article examines the evolution of Indian pharmaceutical manufacturer Cipla toward producing drugs that met the quality standards of European and U.S. regulators. It employs new research in both Cipla's corporate archives and a wide range of oral histories. The article argues that, along with a long-standing corporate culture of self-reliance rooted in nationalism starting from the company's inception in 1935, major factors in Cipla's strategy from the 1960s through the early 2000s included the early adoption and continued use of quality-control technology, along with efforts to create global goodwill for affordable high-quality generic drugs during the HIV/AIDS epidemic of the early 2000s.
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Tanaka, E., E. Inoue, R. Sakai, I. Katsuhiko, A. Shoji, and M. Harigai. "POS0554 MEDICAL COST AND RESOURCE USE IN PATIENTS STARTING TREATMENT FOR RHEUMATOID ARTHRITIS TREATED WITH AND WITHOUT CORTICOSTEROIDS IN JAPAN." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 511.2–512. http://dx.doi.org/10.1136/annrheumdis-2021-eular.2805.
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Background:The 2019 update of the European League Against Rheumatism (EULAR) treatment recommendations strongly recommends co-administration of corticosteroids (CSs) with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) in patients with RA as bridging therapy to improve the success rate of the first-line treatment and to avoid disease flare-ups1; however, current treatment guidelines for RA in Japan do not clearly mention about their use. Poor disease management after the initial diagnosis can affect the overall use of health services and the economic burden on patients.Objectives:To describe medical costs and resource use in patients with early RA treated with and without oral or injectable corticosteroids (CSs) as part of their initial treatment with disease-modifying antirheumatic drugs (DMARDs) in Japan.Methods:We used a large Japanese administrative claims database constructed by the Japan Medical Data Center (JMDC)2. Patients with the International Classification of Diseases 10th revision (ICD-10) codes for RA were enrolled at the first DMARDs prescription after no DMARDs prescription period for 6-months (index date) in the period from 1/1/2012 to 12/31/2017. Patients who were observable for 12 months after the index date as a follow-up period were included. Patients treated with CSs within the follow-up period were compared with those without them (CS and non-CS group). The primary endpoint was mean medical cost per patient in the 12-month follow-up period. The secondary endpoints were costs for drugs, treatments, and materials and the proportions of patients using the subcategories of each resource. Drugs were divided into medications for RA or for comorbidities including adverse events (AEs). Costs in JPY were converted into EUR (1 EUR = 125 JPY in 2020).Results:Eligible patients of 1,670 and 1,487 were identified as the CS and non-CS group (median age: 51 years and 50 years). Total mean costs were significantly higher in the CS group (CS, 4,448 EUR, non-CS 3,208 EUR; P< 0.05). Drug, treatment, and material costs were significantly higher in the CS group than in the non-CS group (drug for RA and AEs, CS 2,367 EUR, non-CS 1,581 EUR, P < 0.05; drug for RA only, CS 2,265 EUR, non-CS 1,516 EUR, P < 0.05; treatment, CS 1,987 EUR, non-CS 1,562 EUR, P < 0.05; material, CS 94 EUR, non-CS 65 EUR; P < 0.05). The resource use in almost all drug subcategories were higher in the CS group (Table 1), as well as in all treatment and material subcategories.Table 1.Number and proportion of patients who used drugsType of drugDrug use, n (%)CS (N = 1,670)Non-CS (N = 1,487)P-valuecsDMARDsTotal1,635 (97.9)1,447 (97.3)0.328 Methotrexate1,481 (88.7)1,315 (88.4)0.870 Others790 (47.3)551 (37.1)< 0.001bDMARDsTotal342 (20.5)181 (12.2)< 0.001 TNFi252 (15.1)129 (8.7)< 0.001 IL6i93 (5.6)40 (2.7)< 0.001 T-cell40 (2.4)17 (1.1)0.012AnalgesicsTotal1,512 (90.5)1,274 (85.7)< 0.001 Acetaminophen379 (22.7)273 (18.4)0.003 Acetaminophen / Opioids84 (5.0)37 (2.5)< 0.001 NSAIDs1,459 (87.4)1,214 (81.6)< 0.001 Opioids16 (1.0)10 (0.7)0.491 Others198 (11.9)101 (6.8)< 0.001AntibioticsTotal1,086 (65.0)873 (58.7)< 0.001 Antibacterial drugs1,022 (61.2)800 (53.8)< 0.001 Antifungal drugs133 (8.0)86 (5.8)0.019 Antiviral drugs172 (10.3)129 (8.7)0.136 Antiparasitic drugs5 (0.3)8 (0.5)0.443Anti-osteoporotic drugs341 (20.4)95 (6.4)< 0.001bDMARDs=biological disease-modifying antirheumatic drugs; CSs=corticosteroids; csDMARDs=conventional synthetic disease-modifying antirheumatic drugs; IL6i=interleukin-6 inhibitor; NSAID=non-steroidal anti-inflammatory drug; T-cell=selective T-cell co-stimulation modulator; TNFi=tumor necrosis factor α inhibitor; P-values were calculated using Chi-square testConclusion:Patients with early RA treated with CSs in the first year after starting DMARDs tended to use more resources and have higher medical costs than patients not treated with CSs.References:[1]Smolen JS et al., Ann Rheum Dis. 2020;79(6):685-699.[2]JMDC claims database, Tokyo, Japan.Disclosure of Interests:Eiichi Tanaka Speakers bureau: AbbVie GK, Asahi Kasei Pharma Corporation, Astellas Pharma Inc, Ayumi Pharmaceutical Corporation, Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., GlaxoSmithKline K.K., Kyowa Pharma Chemical Co., Ltd., Janssen Pharmaceutical K.K., Mochida Pharmaceutical Co., Ltd., Pfizer, Takeda Pharmaceutical Co., Ltd, and Teijin Pharma Ltd., Eisuke Inoue Speakers bureau: Pfizer Japan, Bristol-Myers Squibb K.K., Ryoko Sakai Speakers bureau: Bristol Myers Squibb Co., Ltd., Grant/research support from: Tokyo Women’s Medical University (TWMU), particularly the Division of Multidisciplinary Management of Rheumatic Diseases, Department of Rheumatology, has received unrestricted research grants from Ayumi Pharmaceutical Co.; Chugai Pharmaceutical Co., Ltd.; Eisai Co., Ltd., Nippon Kayaku Co., Ltd.; Taisho Toyama Pharmaceutical Co., Ltd.; Takeda Pharmaceutical Co., Ltd.; Mitsubishi Tanabe Pharma Co.; and Teijin Pharma Ltd., with which TWMU paid the salaries of RS., Iwasaki Katsuhiko: None declared, Ayako Shoji: None declared, masayoshi harigai Speakers bureau: AbbVie GK, Ayumi Pharmaceutical Corporation, Bristol-Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., Pfizer Japan Inc., and Takeda Pharmaceutical Co., Ltd., Consultant of: AbbVie GK, Bristol-Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., and Gilead Sciences Inc., Grant/research support from: AbbVie GK, and Asahi Kasei Corp., Astellas Pharma Inc., Ayumi Pharmaceutical Corporation, Bristol-Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd. Daiichi-Sankyo, Inc., Eisai Co., Ltd., Mitsubishi Tanabe Pharma Corporation., Nippon Kayaku Co., Ltd., Taisho Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Co., Ltd.
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Tanaka, E., E. Inoue, R. Sakai, I. Katsuhiko, A. Shoji, and M. Harigai. "POS0551 MEDICAL COSTS FOR PATIENTS STARTING TREATMENT FOR RHEUMATOID ARTHRITIS WHO HAVE COMORBID DIABETES MELLITUS IN JAPAN." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 510.1–510. http://dx.doi.org/10.1136/annrheumdis-2021-eular.2770.
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Background:Rheumatoid arthritis (RA) patients can experience various comorbidities1. The incidence of diabetes mellitus (DM) is reported higher in patients with RA2 and comorbid DM is likely to affect treatment outcomes3 and then healthcare resource uses, however, no previous study has not focused on it.Objectives:To evaluate medical costs and resource use in patients starting treatment for RA with and without DM using a large claims database in Japan.Methods:We used a large Japanese administrative claims database constructed by the Japan Medical Data Center (JMDC)4. Patients with the International Classification of Diseases 10th revision (ICD-10) codes for RA who started medication with disease-modifying antirheumatic drugs (DMARDs) after 6 months without them in the period from 1/1/2012 to 12/31/2017 and who were observable for 12 months as a follow-up period were enrolled. These patients were categorized as DM or non-DM group with ICD-10 codes for DM plus use of antidiabetic drugs in 6 months before starting DMARDs (baseline period). To adjust baseline characteristics between the 2 groups, they were matched by sex, age, Charlson Comorbidity Index (CCI) except for DM, months from the first RA codes to starting DMARDs, and medications. The primary endpoint was mean medical cost per patient in the 12-month follow-up period. Costs in JPY were converted into EUR (1 EUR = 125 JPY in 2020). Costs for drugs, treatments, and materials and their subcategories were evaluated both with and without DM-specific costs. The secondary endpoints were the proportions of patients using the subcategories of each resource.Results:Patients of 161 for the DM group and 2,974 for the non-DM group were eligible, and 109 patients were matched from each group. The medians of age and CCI were 59 years and 2.0 in both groups and no significant difference was observed in all baseline characteristics used for matching between the groups. Total mean costs were significantly higher in the DM group (DM, 5,331 EUR, non-DM 3,200 EUR; P< 0.05). After excluding DM-specific costs, drug costs were significantly higher in the DM group than in the non-DM group (DM 1,883 EUR, non-DM 896 EUR; P < 0.05), especially costs for biological DMARDs (DM 1,156 EUR, non-DM 292 EUR; P < 0.05), mainly because a higher proportion of patients used these drugs in the DM group (Table 1). Treatment costs (DM 2,380 EUR, non-DM 2,133 EUR) and material costs (DM 74 EUR, non-DM 149 EUR) were not different between the groups, but only costs for examinations were significantly higher in the DM group (DM 970 EUR, non-DM 779 EUR; P < 0.05).Table 1.Number and proportion of patients who used drugsType of drugDrug use, n (%)DM (N = 109)Non-DM (N = 109)P-valuecsDMARDsTotal109 (100.0)109 (100.0)1.000Methotrexate101 (92.7)102 (93.6)1.000Others46 (42.2)51 (46.8)0.583bDMARDsTotal16 (14.7)6 (5.5)0.041TNFi11 (10.1)4 (3.7)0.118IL6i6 (5.5)2 (1.8)0.219T-cell4 (3.7)0 (0.0)0.125tsDMARDs0 (0.0)0 (0.0)1.000CSs65 (59.6)62 (56.9)0.711AnalgesicsTotal103 (94.5)96 (88.1)0.167Acetaminophen24 (22.0)23 (21.1)1.000Acetaminophen /Opioids10 (9.2)6 (5.5)0.454NSAIDs102 (93.6)93 (85.3)0.093Opioids0 (0.0)4 (3.7)0.125Others25 (22.9)17 (15.6)0.185bDMARDs=biological disease-modifying antirheumatic drugs; CSs=corticosteroids; csDMARDs=conventional synthetic disease-modifying antirheumatic drugs; DM=diabetes mellitus; IL6i=interleukin-6 inhibitor; NSAID=non-steroidal anti-inflammatory drug; T-cell=selective T-cell co-stimulation modulator; TNFi=tumor necrosis factor α inhibitor; tsDMARDs=targeted synthetic disease-modifying antirheumatic drugs; P-values were calculated using McNemar testConclusion:Medical costs for RA were higher in the DM group than in the non-DM group because of more prevalent use of biological DMARDs in the DM group.References:[1]Gabriel SE et al., Arthritis Res Ther. 2009;11(3):229.[2]Giacomelli R et al., Expert Rev Clin Immunol. 2016;12(8):849-55.[3]Crepaldi G et al., PLoS One. 2016;11(1):e0146991.[4]JMDC claims database, Tokyo, Japan.Disclosure of Interests:Eiichi Tanaka Speakers bureau: AbbVie GK, Asahi Kasei Pharma Corporation, Astellas Pharma Inc, Ayumi Pharmaceutical Corporation, Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., GlaxoSmithKline K.K., Kyowa Pharma Chemical Co., Ltd., Janssen Pharmaceutical K.K., Mochida Pharmaceutical Co., Ltd., Pfizer, Takeda Pharmaceutical Co., Ltd, and Teijin Pharma Ltd., Eisuke Inoue Speakers bureau: Pfizer Japan, Bristol-Myers Squibb K.K., Ryoko Sakai Speakers bureau: Bristol Myers Squibb Co., Ltd., Grant/research support from: Tokyo Women’s Medical University (TWMU), particularly the Division of Multidisciplinary Management of Rheumatic Diseases, Department of Rheumatology, has received unrestricted research grants from Ayumi Pharmaceutical Co.; Chugai Pharmaceutical Co., Ltd.; Eisai Co., Ltd., Nippon Kayaku Co., Ltd.; Taisho Toyama Pharmaceutical Co., Ltd.; Takeda Pharmaceutical Co., Ltd.; Mitsubishi Tanabe Pharma Co.; and Teijin Pharma Ltd., with which TWMU paid the salaries of RS., Iwasaki Katsuhiko: None declared, Ayako Shoji: None declared, masayoshi harigai Speakers bureau: AbbVie GK, Ayumi Pharmaceutical Corporation, Bristol-Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., Pfizer Japan Inc., and Takeda Pharmaceutical Co., Ltd., Consultant of: AbbVie GK, Bristol-Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., and Gilead Sciences Inc., Grant/research support from: AbbVie GK, and Asahi Kasei Corp., Astellas Pharma Inc., Ayumi Pharmaceutical Corporation, Bristol-Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd. Daiichi-Sankyo, Inc., Eisai Co., Ltd., Mitsubishi Tanabe Pharma Corporation., Nippon Kayaku Co., Ltd., Taisho Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Co., Ltd.
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Kojima, Yuki, Fumihiko Hayakawa, Takanobu Morishita, Keiki Sugimoto, Mizuho Iwase, Hideyuki Yamamoto, Daiki Hirano, Naoto Imoto, Seiji Okada, and Hitoshi Kiyoi. "YM155 Induces Apoptosis through Proteasome-Dependent Degradation of MCL-1 in Primary Effusion Lymphoma." Blood 128, no. 22 (December 2, 2016): 3013. http://dx.doi.org/10.1182/blood.v128.22.3013.3013.
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Abstract Primary effusion lymphoma (PEL) is a subtype of non-Hodgkin lymphoma caused by human herpes virus 8 (HHV-8), which mainly occurs in patients with acquired immunodeficiency. It is highly refractory to conventional chemotherapies, and has a very poor prognosis. We recently developed patient-derived xenograft (PDX) screening, a novel high-throughput drug screening system using PDX cells that were established by transplantations of primary tumor cells into immunodeficient mice and maintained primary cell phenotype. PDX screening is expected to discover anti-tumor drugs that have been overlooked by conventional screenings using cell lines. Here, we performed a PDX screening to develop a new therapeutic agent for PEL. We previously established a PDX and a cell line designated as GTO from the same primary cells of PEL. We performed screenings of a library containing 3518 known pharmacologically active substance and off-patent drugs using the PDX cells (PDX screening) and GTO (Cell-line screening). We compared the results of both screenings and found that PDX cells and cell lines had quite different drug sensitivity profiles. The correlation coefficient between them was 0.67. Twenty-six drugs (0.7%) were at least 2 times more effective for PDX cells than for GTO and designated as PDX-preferred drugs (Figure A). The opposites were named as cell line-preferred drugs and existed 80 (2.2%). We found that PDX-preferred drugs significantly higher activity to induce reactive oxygen species (ROS) production (P<0.001), indicating the sensitivity of PDX cells to oxidative stress. We examined the reproducibility of anti-tumor effect of top 10 compounds of PDX screening in different system including in vivo mouse model and finally selected YM155, a possible survivin inhibitor, as the best candidate for an anti-tumor drug for PEL. It showed strong and dose-dependent anti-tumor effect on both PDX cells and cell lines of PEL. Its GI50 was 7.8 nM in the PDX cells, and 1.2 - 7.9 nM in three kinds of PEL cell lines. YM155 treatment increased the cleavage of caspase-3, caspase-7, and PARP and caused apoptosis of GTO, which was inhibited by a caspase inhibitor, Z-VAD-FMK. Although YM155 was discovered as a survivin inhibitor, we observed that YM155 reduced myeloid cell leukemia-1 (MCL-1) protein prior to survivin reduction by time course experiments. Observed MCL-1 reduction by YM155 was attenuated by a proteasome inhibitor, MG132, suggesting that MCL-1 reduction was due to proteasome-dependent degradation. Furthermore, we confirmed the importance of MCL-1 for survival by its knockdown by siRNA in PEL cell line. Finally, we assessed the in vivo effect of YM155. NOD/SCID/IL-2Rgnull mice were injected intraperitoneally with PEL-PDX cells and were treated with vehicle or YM155 (5mg/kg) from day 1 to 21. YM155 was administered by continuous subcutaneous injection using osmotic pumps. Treatment with YM155 significantly inhibited progression of ascites compared with control mice (Figure B). These results suggested that YM155 was a promising anti-cancer agent for PEL. Figure Figure. Disclosures Sugimoto: Otsuka Pharmaceutical Co., Ltd.: Employment. Kiyoi:Chugai Pharmaceutical Co. LTD.: Research Funding; Alexion Pharmaceuticals: Research Funding; MSD K.K.: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding; Astellas Pharma Inc.: Consultancy, Research Funding; Yakult Honsha Co.,Ltd.: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Fujifilm Corporation: Patents & Royalties, Research Funding; Zenyaku Kogyo Co.LTD.: Research Funding; Phizer Japan Inc.: Research Funding; Novartis Pharma K.K.: Research Funding; Mochida Pharmaceutical Co., Ltd.: Research Funding; Toyama Chemikal Co.,Ltd.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; AlexionpharmaLLC.: Research Funding; JCR Pharmaceutlcals Co.,Ltd.: Research Funding; Nippon Boehringer Ingelheim Co., Ltd.: Research Funding; Celgene Corporation: Consultancy; Eisai Co., Ltd.: Research Funding; Kyowa-Hakko Kirin Co.LTD.: Research Funding.
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Thomas, Mark J., and Robert C. Malenka. "Synaptic plasticity in the mesolimbic dopamine system." Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences 358, no. 1432 (April 29, 2003): 815–19. http://dx.doi.org/10.1098/rstb.2002.1236.
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Long-term potentiation (LTP) and long-term depression (LTD) are thought to be critical mechanisms that contribute to the neural circuit modifications that mediate all forms of experience-dependent plasticity. It has, however, been difficult to demonstrate directly that experience causes long-lasting changes in synaptic strength and that these mediate changes in behaviour. To address these potential functional roles of LTP and LTD, we have taken advantage of the powerful in vivo effects of drugs of abuse that exert their behavioural effects in large part by acting in the nucleus accumbens (NAc) and ventral tegmental area (VTA); the two major components of the mesolimbic dopamine system. Our studies suggest that in vivo drugs of abuse such as cocaine cause long-lasting changes at excitatory synapses in the NAc and VTA owing to activation of the mechanisms that underlie LTP and LTD in these structures. Thus, administration of drugs of abuse provides a distinctive model for further investigating the mechanisms and functions of synaptic plasticity in brain regions that play important roles in the control of motivated behaviour, and one with considerable practical implications.
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Higuchi, T., E. Tanaka, E. Inoue, M. Abe, K. Saka, E. Sugano, N. Sugitani, et al. "AB0286 RETENTION RATE OF BIOLOGIC DISEASE-MODIFYING ANTI-RHEUMATIC DRUGS IN PATIENTS WITH RHEUMATOID ARTHRITIS WITH DECREASED KIDNEY FUNCTION: RESULTS FROM THE IORRA COHORT." Annals of the Rheumatic Diseases 82, Suppl 1 (May 30, 2023): 1324. http://dx.doi.org/10.1136/annrheumdis-2023-eular.374.
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BackgroundWe previously reported that rheumatoid arthritis (RA) patients with chronic kidney disease (CKD) were at increased risk of failure to achieve remission and of occurrence of hospitalized infections [1]. Although biologic disease-modifying anti-rheumatic drugs (bDMARDs) are a promising treatment option, their effectiveness and safety for this population have not been fully evaluated to date.ObjectivesTo determine the optimal bDMARD selection for treatment of RA patients with decreased kidney function, we compared the retention rates of patients receiving tumor necrosis factor inhibitor (TNFi), interleukin-6 inhibitor (IL-6i), and abatacept (ABT) in RA patients using data from the IORRA cohort, the real-world data registry of Japanese RA patients.MethodsRenal function was calculated using the Japanese versions of the equations for estimated glomerular filtration ratio (eGFRcr). Deceased renal function was defined as eGFRCr<60 mL/min/1.73m2. Among RA patients enrolled in the IORRA cohort between 2003 and 2020, data from patients with decreased kidney function who started bDMARDs were extracted. Renal function and use of bDMARDs by the extracted patients were identified in their medical records. Reasons for discontinuation were classified as ineffectiveness, adverse events caused by bDMARDs, or other reasons. Retention rates due to ineffectiveness or adverse events caused by TNFi (adalimumab or adalimumab biosimilar [ADA], certolizumab pegol [CZP], etanercept or etanercept biosimilar [ETN], golimumab [GLM], infliximab or infliximab biosimilar [IFX]), IL-6i (tocilizumab [TCZ], sarilumab [SAR]) and ABT spanning 36 months were calculated using the Kaplan-Meier method, and adjusted hazard ratio [aHR] of discontinuation of each bDMARD was calculated using the Cox proportional hazard model, with adjustments for age, sex, disease duration, clinical disease activity index (CDAI), methotrexate (MTX)/ prednisolone (PSL) use, and previous bDMARD use at baseline.ResultsA total of 238 treatment courses administered to 191 patients with decreased renal function were included. Median eGFRCrwas 52.5 mL/min/1.73m2(interquartile range: 43.3–57.4). The numbers of bDMARD users were as follows: TNFi, 143 (ADA, 15; CZP, 5; ETN, 67; GLM, 30; IFX, 26); IL-6i, 59 (all were TCZ); and ABT, 36, respectively. ABT users were older than IL-6i users, and TNFi users had higher eGFRCrand a higher proportion of MTX and previous DMARD use than the other groups. Sex, seropositivity, CDAI, health assessment questionnaire, and the proportion of PSL use were similar between groups. The retention rates at 36 months were 59.9%, 72.9%, and 61.7% for TNFi, IL-6i, and ABT, respectively. aHR of discontinuation when TNFi served as reference was 0.60 (95% confidence interval: 0.32–1.10) for IL-6i, and 0.85 (95% confidence interval: 0.44–1.64) for ABT.ConclusionBecause the retention rate of IL-6i was numerically high compared with TNFi and ABT in this study, IL-6i may offer a treatment advantage in RA patients with decreased renal function.Reference[1] Higuchi et al. Mod Rheumatol. 2022;32(5):875–884.Figure 1.The Kaplan-Meier curve of the retention rates of bDMARDs in patients with RA with decreased renal function.AcknowledgementsWe would like to thank Editage (www.editage.com) for English language editing. This work was supported by a research grant from the Ministry of Health, Labour and Welfare (20FC1044).Disclosure of InterestsTomoaki Higuchi: None declared, Eiichi Tanaka Speakers bureau: AbbVie Japan GK; Asahi Kasei Corp.; Astellas Pharma Inc.; Ayumi Pharmaceutical Co.; Chugai Pharmaceutical Co., Ltd.; Eisai Co., Ltd.; Eli Lilly Japan K.K.; GlaxoSmithKline K.K.; Kyowa Pharma Chemical Co., Ltd.; Janssen Pharmaceutical K.K.; Mochida Pharmaceutical Co., Ltd.; Pfizer Japan Inc.; Takeda Pharmaceutical Co., Ltd.; and Teijin Pharma Ltd., Eisuke Inoue Speakers bureau: Bristol Myers Squibb Co., Ltd.; Pfizer Japan Inc.; Nippontect systems Co., Ltd.; RCR Co., Ltd., Mai Abe: None declared, Kumiko Saka: None declared, Eri Sugano: None declared, Naohiro Sugitani: None declared, higuchi yoko: None declared, Moeko Ochiai: None declared, Rei Yamaguchi: None declared, Katsunori Ikari Speakers bureau: Asahi Kasei Corp.; Astellas Pharma Inc.; AbbVie Japan GK; Ayumi Pharmaceutical Co.; Bristol Myers Squibb Co., Ltd.; Chugai Pharmaceutical Co., Ltd.; Eisai Co., Ltd.; Eli Lilly Japan K.K.; Janssen Pharmaceutical K.K.; Kaken Pharmaceutical Co. Ltd.; Mitsubishi Tanabe Pharma Co.; Pfizer Japan Inc.; Takeda Pharmaceutical Co. Ltd.; Teijin Pharma Ltd.; and UCB Japan Co. Ltd., Yamanaka Hisashi Consultant of: CorEvitas LLC, Masayoshi Harigai Speakers bureau: AbbVie Japan GK; AstraZeneca K.K.; Ayumi Pharmaceutical Co.; Boehringer Ingelheim Japan Inc.; Bristol Myers Squibb Co., Ltd.; Chugai Pharmaceutical Co., Ltd.; Eisai Co., Ltd.; Eli Lilly Japan K.K.; GlaxoSmithKline K.K.; Gilead Sciences Inc.; Janssen Pharmaceutical K.K.; Kissei Pharmaceutical Co., Ltd.; Nippon Kayaku Co., Ltd.; Nippon Shinyaku Co., Ltd.; Novartis Japan; Pfizer Japan Inc.; CIMIC Holdings Co., Ltd.; Mitsubishi Tanabe Pharma Co.; Teijin Pharma Ltd.; and UCB Japan Co. Ltd., Consultant of: AbbVie; Boehringer-Ingelheim; Bristol Myers Squibb Co.; Kissei Pharmaceutical Co., Ltd.; and Teijin Pharma Ltd., Grant/research support from: AbbVie Japan GK; Asahi Kasei Corp.; Astellas Pharma Inc.; Ayumi Pharmaceutical Co.; Boehringer Ingelheim Japan, Inc.; Bristol Myers Squibb Co., Ltd., Chugai Pharmaceutical Co., Daiichi-Sankyo, Inc., Eisai Co., Ltd.; Kaken Pharmaceutical Co., Ltd.; Kissei Pharmaceutical Co., Ltd.; Mitsubishi Tanabe Pharma Co.; Nippon Kayaku Co., Ltd.; Sekisui Medical; Taisho Pharmaceutical Co., Ltd.; and Teijin Pharma Ltd.
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Wright, W. B. "Drugs, ageing, and society Burns Bruce Phillipson Chris Drugs, ageing, and society Croom Helm Ltd, Beckenham, 1986, 180pp, H/B, £19.95." Elderly Care 7, no. 4 (April 1987): 28. http://dx.doi.org/10.7748/eldc.7.4.28.s27.
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Saliy, O. O., and M. O. Sinchuk. "DEVELOPMENT OF APPROACHES TO LABORATORY CONTROL OF «BIOTESTLAB» LTD TO ENSURE QUALITY OF VETERINARY PREPARATIONS." Scientific and Technical Bulletin оf State Scientific Research Control Institute of Veterinary Medical Products and Fodder Additives аnd Institute of Animal Biology 22, no. 2 (October 7, 2021): 331–38. http://dx.doi.org/10.36359/scivp.2021-22-2.39.
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The article presents the development of approaches to laboratory control and the results of research related to the standardization of methods at Ltd "BIOTESTLAB" to ensure the quality of veterinary drugs. Attention is paid to the methods of biological quality control of veterinary drugs: microbiological purity, hemagglutination reaction (HAR), determination of infectious activity of embryonic vaccines. Because such methods are characterized by low automation, low accuracy, the impact on the result of error due to personnel performing operations manually, the lack of regulatory approaches to validation of methods. The influence on the reliability of the obtained results on determining the titer of infectious activity of the virus of the following factors: quality and concentration of the applied suspension of erythrocytes of a rooster, duration of cultivation of a virus, technique of performance by the controller of each operation of a technique is investigated. Studies on the influence of these factors were conducted on the example of determining the titer of infectious activity of Newcastle disease virus. Approaches to accounting for the obtained results by the method of qualitative HAR, namely visual control of hemagglutination reaction on glass and on a plate are established. A comparative characterization of the results for the detection of hem agglutinin of Newcastle disease virus on glass (using 2% suspension of erythrocytes) and on the plate (using 1% suspension of erythrocytes). The results of inter-laboratory comparative tests of microbiological methods conducted to verify the qualification and reliability of the results are presented. It is demonstrated that the proper organization of laboratory control in measures to confirm the results of control of quantitative methods and evaluation of biological material by standardizing methods, conducting internal laboratory testing and participation in inter-laboratory comparative tests ensures and guarantees the quality of veterinary drugs.
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Jaquette, Ian. "Merck KGaA v. Integra Lifesciences I, Ltd: Implications of the Supreme Court's Decision for the People Who Matter Most … the Consumer." American Journal of Law & Medicine 33, no. 1 (March 2007): 97–117. http://dx.doi.org/10.1177/009885880703300103.
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Sales of brand and generic pharmaceuticals in the United States reached $274.7 billion in 2006. Consumers in this country, including the federal government, are paying tremendous amounts of money for drugs and the cost continues to be a growing concern for all parties involved. Part of this increased cost encountered by consumers can be directly attributed to the ever-increasing costs manufacturers must cope with in the development of new drugs. Economists estimate that it takes twelve to fifteen years to develop a single new drug and have it approved by the Food and Drug Administration (“FDA”). The average cost: $800 million. For every 10,000 compounds investigated, only five are ever tested as potential medicines in clinical trials and only one is ever approved for patient use. Of all the drugs approved by the FDA, only three out of ten generate revenues that meet or exceed average research and development costs.
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Derkach, I. "Сучасні тенденції на вітчизняному ринку ферумвмісних препаратів для тварин." Scientific Messenger of LNU of Veterinary Medicine and Biotechnologies 19, no. 78 (April 6, 2017): 23–25. http://dx.doi.org/10.15421/nvlvet7805.
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The article presents an analysis of the domestic market of veterinary preparations of Ferum. It is established that nowadays it is represented by 13 drugs of the following group: QV03A Antianemic agents. Preparations of iron, according to ATS-vet classification. Assortment of 38% is provided by pharmaceutical goods of Ukrainian producers: «O.L.KAR-AgroZoOvetService», PP Farmaton, LLC «BROVAFARMA», Ltd. «Research and experimental production Institute of Epizootology», PP «BIOFARM», LLC «Vetsintez». Imported products (62%) are presented by Pharmacosmos A/S (Kingdom Denmark), MERIEL, KOOFAVET C.A.C. (France), Wagen B & G Co., Ltd. (Southern Korea), Bovet Pulawi Cp. with oh (Poland), Interchemy Werken «De Adelaar» Esti AS (Estonia), Biowet, a.s. (Czech Republic). In the composition of modern drugs, the dextran complex of ferric hydroxide (III) is used. Its combination with other active substances is included into 46% of medicines. Preparations, such as Intrafer-100 B12, Intrafer-200-B12, Ferovita-200, Ferrovet+B12 also contain cyanocobalamin.Vitamins of other groups, macro- and micronutrients, inactivated normal pig blood serum are contained in GAFFERWIT (Biowet, Czech Republic) and Soiferovit (Bilovet Pulawi, Poland). Among the above-mentioned drugs only FERROVET + B12 is produced in Ukraine (LLC «Vetsintez»).
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Rybachuk, Zh V., I. V. Prisyazhnyuk, and K. O. Chirta-Sinelnyk. "“EMBIOTIC” Ltd. “EM-Ukraine” – an alternative to antibiotic therapy for digestive disorders in calves." Scientific Messenger of LNU of Veterinary Medicine and Biotechnologies 23, no. 102 (March 30, 2021): 8–13. http://dx.doi.org/10.32718/nvlvet10202.
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The prophylactic efficacy of diarrhea in calves with different methods and doses of feed additive “EMBIOTIC” during the first 14 days of life was studied. Almost 50 % of dairy calves had symptoms of diarrhea. Effective treatment regimens for such animals included one of the antibiotics (azithromycin or 15 % amoxicillin emulsion) and, if necessary, sulfonamide drugs (trimeratinvet with the drugs sulfadimesine and trimethoprim) or the drug sulfate lozin, which includes sulfonamide and antibiotics (tylosin tartrate, oxytetracycline, sulfadimesine, trimethoprim). Simultaneously, symptomatic therapy was performed with the use of refinery – 10 % solution of ketoprofen in the form of the drug ketonil, which provided analgesia and reduction of body temperature to physiological limits. Еhere is always a drug cyanophore (LR butaphosphane and cyanocobalamin) as a general stimulant in the scheme. To conduct the experiment, 5 groups of animals were formed, 6 in each, age – the first day after birth. From the first to the 14th day of life, from the first or second colostrum, each calf from different groups was given daily 5 cm3, 10 cm3 and 15 cm3 of feed additive “EMBIOTIC”, respectively. The fourth experimental group – control (probiotic was not received), and the fifth – calves obtained from cows, which 10–14 days before and after calving daily with feed or water received 80–100 cm3 of feed additive “EMBIOTIC”, and calves the tested drug was not used. During the experiment twice a day (morning and evening), clinical observation and examination of calves of all experimental groups. Two days later, calves that received 5 cm3, 10 cm3 and 15 cm3 of feed additive “EMBIOTIC” were registered to improve appetite, increased mobility and prolonged and pronounced sleep. In animals that received with milk 10 cm3 and 15 cm3 of feed additives, during the observation period, disorders of the digestive system were not registered. Two calves, receiving 5 cm3 of EMBIOTICS daily, had symptoms of minor diarrhea for only 12 days, but there was no appetite. After 24 hours, the symptoms of indigestion went away on their own without the use of any drugs. Newborn calves obtained from cows that received “EMBIOTIC” as part of their diet or water were rated 9–10 on the Apgar scale. From the 3rd day they ate straw and they registered chewing gum for 3.7 ± 0.2 days of life. Within 14 days of observation of disorders of the gastrointestinal tract, they were not registered. Thus, the feed additive “EMBIOTIC” provides prevention of diarrhea in calves.
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Poteshkina, N. G., and A. A. Troshina. "Torasemid in the treatment of cardiovascular disease: the optimal use in conditions of comorbidity." Systemic Hypertension 12, no. 4 (December 15, 2015): 38–41. http://dx.doi.org/10.26442/sg29113.
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The article reviews the current clinical data on the use of one of the modern pharmacological drugs torasemide (Diuver, Teva Pharmaceutical Industries Ltd., Israel) in the treatment of cardiovascular disease in conditions of comorbidity. Presents a comprehensive view of the problem identified and a reasoned approach to the choice of diuretic therapy with clinico-pathophysiological substantiation of the use of a loop diuretic torasemid. Conceptually formed of a number of provisions on the application of one of the modern diuretic drugs in therapeutic practice in patients with arterial hypertension and heart failure.
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Ochiai, M., E. Tanaka, E. Inoue, M. Abe, E. Sugano, N. Sugitani, K. Saka, et al. "THU0144 DESCRIPTIVE ANALYSIS OF PREGNANCY, DELIVERY, AND LACTATION IN PATIENTS WITH RHEUMATOID ARTHRITIS FROM THE IORRA COHORT." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 287–88. http://dx.doi.org/10.1136/annrheumdis-2020-eular.2692.
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Background:Rheumatoid Arthritis (RA) is common in women with reproductive age. For this reason, RA treatment during pregnancy and lactation is very important. In recent years, the use of biologic disease-modifying antirheumatic drugs (bDMARDs) has become common in RA treatment (1), treatment during pregnancy and lactation has changed drastically (2,3).Objectives:To investigate the pregnancy, delivery and lactation status of RA patients and treatment during that period in daily practice.Methods:The IORRA cohort is a large, single institute-based, observational cohort of RA patients established at Institute of Rheumatology, Tokyo Women’s Medical University, in 2000. We identified female RA patients aged 20-49 years who answered ‘pregnant’ or ‘delivered’ in the IORRA survey in 2010-2016 and whose pregnancies were confirmed in the medical records. We examined the Disease Activity Score with 28 joint count (DAS28)-CRP, medication use situation, the outcome of pregnancy, and lactation in those patients.Results:A total of 101 patients and 143 pregnancies were confirmed, of which 136 outcomes of pregnancy could be confirmed in the medical records. Among 136 confirmed pregnancy cases, there were 106 births and 30 miscarriages. Among 106 births, 4 cases (3.8%) were birth defects that could be confirmed in the medical records. The average age at pregnancy was 34.2±3.7 years and 36.1±3.3 years in delivered and miscarried cases, respectively. Miscarried cases were significantly older pregnancies (p=0.01). Of the 106 births, 65 birth weeks were confirmed, with an average of 37.9±1.8 weeks. The number of preterm delivery was 11 cases (16.9%). The average birth weight of 59 babies whose birth weight could be confirmed was 2699±517 g. There were 21 cases (35.6%) of low birth weight infants. The proportion of patients in DAS28-CRP remission was 73.1% before pregnancy, 61.6% during pregnancy, and 68.0% 1 year after delivery. Drugs used before pregnancy were glucocorticoid (48.8%), non-steroidal anti-inflammatory drugs (14.2%), conventional synthetic DMARDs (24.8%), and bDMARDs (48.0%). Etanercept accounted for 90% of bDMARDs. Among taking bDMARDs patients, 73.8% were discontinued after the pregnancy, and 26.2% were continued during pregnancy. Among those patients who continued bDMARDs, lactating patients were 12/26 (46.2%) cases after delivery, 10/30 (33.3%) cases in six months after delivery, and 7/36 (19.4%) cases in 1 year after delivery, respectively.Conclusion:The actual situation of pregnancy, delivery, and lactation in RA patients was revealed. Especially, bDMARDs were used at relatively high rates in RA patients who wish to have a child.References:[1]Lancet. 2017;10;389:2338-2348.[2]Semin Arthritis Rheum. 2019;49:S32-S35.[3]Rheumatology. 2016;55:1693-7.Disclosure of Interests:Moeko Ochiai: None declared, Eiichi Tanaka Consultant of: ET has received lecture fees or consulting fees from Abbvie, Asahi Kasei pharma co., Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo Co., Eisai Pharmaceutical, Janssen Pharmaceutical K.K., Nippon Kayaku, Pfizer, Takeda Pharmaceutical, Taisho Toyama Pharmaceutical Co., and UCB Pharma., Speakers bureau: ET has received lecture fees or consulting fees from Abbvie, Asahi Kasei pharma co., Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo Co., Eisai Pharmaceutical, Janssen Pharmaceutical K.K., Nippon Kayaku, Pfizer, Takeda Pharmaceutical, Taisho Toyama Pharmaceutical Co., and UCB Pharma., Eisuke Inoue Speakers bureau: EI has received speaker fee from Bristol-Meyers, Pfizer, Merck serono., Mai Abe: None declared, Eri Sugano: None declared, Naohiro Sugitani: None declared, Kumiko Saka: None declared, higuchi yoko: None declared, Rei Yamaguchi: None declared, Naoki Sugimoto: None declared, Ikari Katsunori Speakers bureau: KI has received speaker’s fee from Asahi Kasei Pharma Corp., Astellas Pharma Inc., AbbVie Japan GK, Ayumi Pharmaceutical Co., Bristol Myers Squibb Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eis, ai Co., Ltd., Eli Lilly Japan K.K., Janssen Pharmaceutical K.K., Kaken Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Corp.Pfizer Japan Inc., Takeda Pharmaceutical Co. Ltd., Teijin Pharma Ltd and UCB Japan Co. Ltd., Ayako Nakajima Grant/research support from: AN has received research grants from Chugai Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Consultant of: AN has consultant fee from Nippon Kayaku Co. Ltd., Speakers bureau: AN has received speaker’s fee from AbbVie Japan GK, Actelion Pharmaceuticals Japan LTD., Asahi Kasei Pharma Co., Astellas Pharma Inc., Ayumi Pharmaceutical Co., Bristol Myers Squibb Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., GlaxoSmithKline K.K., Hisamitsu Pharmaceutical Co. Inc., Kyorin Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Co., Otsuka Pharmaceutical Co. Ltd., Pfizer Japan Inc., and Teijin Pharma Ltd., Atsuo Taniguchi: None declared, Hisashi Yamanaka Grant/research support from: HY has received research grant or speaker fee from AbbVie, Astellas, Ayumi, Behringer, Bristol-Meyers, Chugai, Daiichi-Sankyo, Eisai, Kaken, Nippon-Shinyaku, Novartis, Ono, Pfizer, Taisyo-Toyama, Takeda, Tanabe-Mitsubishi, Teijin Pharma, Torii, UCB, YLbio., Speakers bureau: HY has received research grant or speaker fee from AbbVie, Astellas, Ayumi, Behringer, Bristol-Meyers, Chugai, Daiichi-Sankyo, Eisai, Kaken, Nippon-Shinyaku, Novartis, Ono, Pfizer, Taisyo-Toyama, Takeda, Tanabe-Mitsubishi, Teijin Pharma, Torii, UCB, YLbio., masayoshi harigai Grant/research support from: AbbVie Japan GK, Ayumi Pharmaceutical Co., Bristol Myers Squibb Co., Ltd., Eisai Co., Ltd., Mitsubishi Tanabe Pharma Co., Nippon Kayaku Co., Ltd., and Teijin Pharma Ltd. MH has received speaker’s fee from AbbVie Japan GK, Ayumi Pharmaceutical Co., Boehringer Ingelheim Japan, Inc., Bristol Myers Squibb Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., GlaxoSmithKline K.K., Kissei Pharmaceutical Co., Ltd., Oxford Immuotec, Pfizer Japan Inc., and Teijin Pharma Ltd. MH is a consultant for AbbVie, Boehringer-ingelheim, Kissei Pharmaceutical Co., Ltd. and Teijin Pharma.
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Hindmarch, Ian. "Psychiatric drugs explained D. Healy. Mosby?Yearbook Ltd., 1993. 284 pp. �7.95. ISBN 0-7234-1845-4." Human Psychopharmacology: Clinical and Experimental 8, no. 4 (July 1993): 293. http://dx.doi.org/10.1002/hup.470080410.
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Linden, David J. "A late phase of LTD in cultured cerebellar Purkinje cells requires persistent dynamin-mediated endocytosis." Journal of Neurophysiology 107, no. 1 (January 2012): 448–54. http://dx.doi.org/10.1152/jn.00824.2011.
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Long-term synaptic depression (LTD) of cerebellar parallel fiber-Purkinje cell synapses is a form of use-dependent synaptic plasticity that may be studied in cell culture. One form of LTD is induced postsynaptically through an mGlu1/Ca influx/protein kinase Cα (PKCα) cascade, and its initial expression requires phosphorylation of ser-880 in the COOH-terminal PDZ-ligand region of GluA2 and consequent binding of PICK1. This triggers postsynaptic clathrin/dynamin-mediated endocytosis of GluA2-containing surface AMPA receptors. Cerebellar LTD also has a late phase beginning 45–60 min after induction that is blocked by transcription or translation inhibitors. Here, I have sought to determine the expression mechanism of this late phase of LTD by applying various drugs and peptides after the late phase has been established. Neither bath application of mGluR1 antagonists (JNJ-16259685, LY-456236) nor the PKC inhibitor GF-109203X starting 60–70 min after LTD induction attenuated the late phase. Similarly, achieving the whole cell configuration with a second pipette loaded with the peptide PKC inhibitor PKC(19–36) starting 60 min postinduction also failed to alter the late phase. Late internal perfusion with peptides designed to disrupt PICK1-GLUA2 interaction or PICK1 dimerization failed to impact late phase LTD expression. However, late internal perfusion with two different blockers of dynamin, the drug dynasore and a dynamin inhibitory peptide (QVPSRPNRAP), produced rapid and complete reversal of cerebellar LTD expression. These findings suggest that the protein synthesis-dependent late phase of LTD requires persistent dynamin-mediated endocytosis, but not persistent PICK1-GluA2 binding nor persistent activation of the upstream mGluR1/PKCα signaling cascade.
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Bach, K. B., and G. S. Mitchell. "Hypercapnia-induced long-term depression of respiratory activity requires α2-adrenergic receptors." Journal of Applied Physiology 84, no. 6 (June 1, 1998): 2099–105. http://dx.doi.org/10.1152/jappl.1998.84.6.2099.
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We investigated the effects of repeated hypercapnic episodes (inspired CO2fraction = 0.10) on posthypercapnic respiratory nerve discharge. Anesthetized (urethan), vagotomized, and artificially ventilated rats were presented with three consecutive 5-min episodes of hyperoxic hypercapnia, separated by 5 min of hyperoxic normocapnia (inspired O2 fraction = 0.5). Respiratory nerve discharge and blood gases were recorded before and 30 and 60 min after the final hypercapnic episode. Posthypercapnia, arterial[Formula: see text] was maintained within 1 Torr of initial baseline values. Integrated phrenic and hypoglossal burst amplitudes decreased posthypercapnia by up to 46 ± 17 and 55 ± 13% of baseline values, respectively, and remained reduced for at least 1 h [long-term depression (LTD)]. The protocol was repeated in rats pretreated with the α2-adrenergic antagonists yohimbine HCl (0.5 mg/kg; n = 7) or 2-[2-(2-methoxy-1,4-benzodioanyl)]imidazoline (RX-821002) HCl (0.25 mg/kg; n = 3). Both drugs attenuated LTD in the phrenic and hypoglossal neurograms. Results indicate that episodic hypercapnia elicits a yohimbine- and RX-821002-sensitive LTD of respiratory nerve activity in rats, suggesting that LTD requires α2-receptor activation.
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Venetikou, Maria S., Jacky M. Burrin, Christine A. Woods, Tom H. Yeo, Judith Brownell, and Eric F. Adams. "Effects of two novel dopaminergic drugs, CV 205-502 and CQP 201-403, on prolactin and growth hormone secretion by human pituitary tumours in vitro." Acta Endocrinologica 116, no. 2 (October 1987): 287–92. http://dx.doi.org/10.1530/acta.0.1160287.
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Abstract. Two novel dopaminergic drugs, designated CV 205-502 and CQP 201-403 have recently been developed by Sandoz Pharmaceuticals Ltd (Basle, Switzerland). The effects of these drugs on PRL and GH secretion by normal rat and tumorous human pituitary cells in vitro have been investigated. Low doses of both CV 205-502 and CQP 201-403 immediately and profoundly suppressed PRL secretion, which failed to recover up to 7 h after removal of the drugs. Similarly, CQP 201-403 significantly suppressed basal GH secretion by human pituitary somatotropic tumours in culture, and both drugs significantly reduced the stimulatory effect of GHRH. These effects are more potent and longer acting than the previously described in vitro effects of bromocriptine. It is concluded that CV 205502 and CQP 201-403 hold potential for the treatment of patients with hyperprolactinaemia and, possibly, also in patients with acromegaly.
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Kawazoe, M., K. Aoki, W. Hirose, S. Masuoka, K. Kaneko, J. Nishio, E. Watanabe, K. Furukawa, M. Kanaji, and T. Nanki. "AB1328 LONGITUDINAL SEROLOGICAL STUDY OF ANTI-SARS-CoV-2 SPIKE PROTEIN ANTIBODIES AFTER TWO DOSES OF mRNA VACCINES IN PATIENTS WITH RHEUMATIC DISEASES: ANALYSIS OF EFFECTS OF IMMUNOSUPPRESSANT THERAPY." Annals of the Rheumatic Diseases 82, Suppl 1 (May 30, 2023): 1893.1–1894. http://dx.doi.org/10.1136/annrheumdis-2023-eular.1217.
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BackgroundThe longitudinal efficacy and safety data of vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in patients with rheumatic disease (RD) remains unclear.ObjectivesThe objective of the study was to examine changes over time in anti-SARS-CoV-2 spike protein IgG (anti-S IgG) values in RD patients compared with controls and investigate the effects of immunosuppressants on the values. Safety of vaccine was also evaluated.MethodsRD patients receiving glucocorticoids or immunosuppressants who were scheduled to receive two doses of SARS-CoV-2 mRNA vaccines were included. Patients not receiving these drugs and were attending the hospital for diseases other than RD or malignancies served as the control group (CG). Following the guidance of the American College of Rheumatology, some immunosuppressive drugs were withheld before and after vaccinations. Blood samples were collected before and 1, 3, and 6 months (M1, M3, M6) after the vaccinations, and anti-S IgG values were measured using SARS-CoV-2 IgG II Quant Reagent Kit (Abbott Laboratories, USA).ResultsBNT162b2 mRNA vaccine-received 289 RD patients {mean age 66.9 [standard deviation (SD), 12.6] years; 241 females and 48 males} and 33 controls (mean age 70.7 [SD, 7.8] years; 22 females and 11 males) were mainly analyzed. Anti-S IgG values markedly increased in both groups at M1 [CG; 9751.5 (2385.3 – 21506.1), RD; 2300.8 (188.5 – 7671.7) AU/mL, expressed as median (25th to 75th percentiles)], subsequently decreased, and were significantly lower in the RD group than in the CG at all time points [CG; 5012.2 (2933.3 – 6628.4), RD; 1505.0 (459.0 – 3229.0) at M3, CG; 1353.6 (505.8 – 1910.3), RD; 402.0 (130.5 – 836.2) at M6]. Regarding antibody positivity, all patients in the CG tested positive at all time points. The antibody positivity rate was significantly lower in the RD group (85.0% at M1, 92% at M3, 86.4% at M6). In comparisons by disease, anti-S IgG values were significantly lower in patients with rheumatoid arthritis, systemic lupus erythematosus, vasculitis and dermatomyositis/polymyositis. In comparisons by treatment, anti-S IgG values were significantly lower in patients receiving rituximab [8.9 (5.8 – 68.2) at M1, 51.7 (26.4 – 144.0) at M3, 45.3 (23.1 – 67.4) at M6], mycophenolate mofetil [258.4 (1.1 – 713.7), 395.1 (18.0 – 2096.1), 212.3 (14.2 – 458.9)], cytotoxic T lymphocyte-associated antigen 4-immunoglobulin (CTLA4-Ig) [336.8 (33.5 – 1166.7), 324.9 (111.2 – 480.6), 84.0 (37.9 – 118.7)], and prednisolone (PSL) [449.4 (26.3 – 2920.1), 709.6 (135.3 – 2008.5), 201.4 (44.7 – 602.5)]. A multivariate analysis with a linear mixed model indicated that there was a significant inverse association between age and the extent of changes in anti-S IgG values from M1, indicating greater decreases in antibody values at an older age from M1 [-75 (-133 – -18), expressed as regression coefficient (95% confidence interval)]. The extent of the decrease in anti-S IgG values was also significantly greater in males [-1873 (-3604 – -142)] and patients treated with PSL [-2071 (-3590 – -551)], CTLA4-Ig [-4018 (-6606 – -1429)], TNF inhibitors [-2009 (-3861 – -157)], and IL-6 inhibitors [-2422 (-4488 – -355)]. Adverse reactions were similar in both the CG and RD group.ConclusionThese results showed that SARS-CoV-2 mRNA vaccination is effective and safe in patients with RD treated with a variety of immunosuppressants. However, even following the ACR guidance on withholding dugs, anti-S IgG values were lower and significantly decreased over time depending on disease and immunosuppressive drugs. Therefore, relative short-term repetitive vaccination might be warranted in patients with RD receiving immunosuppressive drugs.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsMai Kawazoe Speakers bureau: Ayumi Pharmaceutical Corporation, Asahi Kasei Pharma Corp, AstraZeneca K.K., Gilead Sciences Inc and GlaxoSmithKline K.K., Kotaro Aoki: None declared, Wataru Hirose Speakers bureau: Pfizer Japan Inc., Asahikasei Pharma Corp., Chugai Pharmaceutical Co., AbbVie GK and Mitsubishi-Tanabe Pharma Co., Shotaro Masuoka: None declared, Kaichi Kaneko Speakers bureau: Asahi Kasei Pharma Corp, AstraZeneca K.K.,Boehringer Ingelheim Co., Ltd., Daiichi Sankyo Co., Ltd., Eli Lilly Japan K.K.,Gilead Sciences Inc, GlaxoSmithKline K.K., Janssen Pharmaceutical K.K., Novartis Pharma K.K. and Pfizer Japan Inc., Grant/research support from: Asahi Kasei Pharma Corp, Boehringer Ingelheim Co., Ltd. and Daiichi Sankyo Co., Ltd., Junko Nishio Speakers bureau: Asahi KASEI Pharma and Taisho Pharmaceutical Holdings., Grant/research support from: Asahi KASEI Pharma, CHUGAI PHARMACEUTIAL CO., LTD., ONO PHARMACEUTIAL CO., LTD., Boehringer Ingelheim, Nippon KAYAKU CO., AYUMI Pharmaceutical CO., Abbvie GK, Abbott Japan LLC and Taisho Pharmaceutical Holdings., Eri Watanabe Grant/research support from: GlaxoSmithKline K.K., Karin Furukawa: None declared, Miwa Kanaji: None declared, Toshihiro Nanki Speakers bureau: Eisai Co., Ltd., Astellas Pharma Inc., Janssen Pharmaceutical K.K., Ayumi Pharmaceutical Corporation, Pfizer Japan Inc., Asahikasei Pharma Corp., Eli Lilly Japan K.K., Takeda Pharmaceutical Co., Nippon Boehringer Ingelheim Co., Ltd., isho Pharmaceutical Co., Ltd., UCB Japan Co., Ltd., Ono Pharmaceutical Co., Ltd., AstraZeneca K.K., Mochida Pharmaceutical Co., Ltd., GlaxoSmithKline plc., and AbbVie GK., Consultant of: UCB Japan Co., Ltd., Eisai Co., Ltd., and Chugai Pharmaceutical Co., Grant/research support from: Chugai Pharmaceutical Co., Eisai Co., Ltd., Teijin Pharma Ltd., Eli Lilly Japan K.K., Bristol-Myers K.K., Ono Pharmaceutical Co., Ltd., Asahikasei Pharma Corp., Mitsubishi-Tanabe Pharma Co., Ayumi Pharmaceutical Corporation, Shionogi & Co., Ltd., Nippon Kayaku Co., Ltd., AbbVie GK, Nippon Boehringer Ingelheim Co., Ltd., Abbott Japan LLC and Taisho Pharmaceutical Co., Ltd.
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West, Robert. "Say Why to Drugs: Everything You Need to Know About the Drugs We Take and Why We Get HighSuziGageLondon: Hodder & Stoughton Ltd, 2020, ISBN: 9781473686229." Addiction 115, no. 10 (March 21, 2020): 1980–81. http://dx.doi.org/10.1111/add.15034.
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Novak, Barbara V. "How Drugs Work – Basic Pharmacology for Healthcare Professionals Hugh McGavock Published by Radcliffe Publishing Ltd (Third Revised Edition)." Nurse Prescribing 9, no. 2 (February 2011): 88. http://dx.doi.org/10.12968/npre.2011.9.2.88.
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Rae, Ian D. "Responses by Australian pharmacologists to respiratory depression caused by opiates and barbiturates." Historical Records of Australian Science 33, no. 1 (January 17, 2022): 1–11. http://dx.doi.org/10.1071/hr21005.
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In the middle of the last century, pharmacologists at the University of Melbourne led by Professor Frank Shaw inadvertently discovered that an amino-acridine they were using in other experiments reversed the respiratory depressive effects of morphine. They widened their search for such activity, experimenting with a range of heterocyclic substances and achieving success with a thiazole derivative, provided to them by the Professor of Organic Chemistry at the university, that countered the effects of morphine. Working with chemists and pharmacologists at a company with which Shaw had close links, Nicholas Pty Ltd, they discovered a glutarimide that offered the same benefit in cases of barbiturate intoxication. While this collaboration between pharmacologists and chemists, in industry and university, promised much, neither of these drugs survived into modern medical practice. The reasons for this include the development of better drugs or more appropriate patient care, Shaw’s withdrawal from the work because of illness, and decisions in the company that might have been influenced by increasingly stringent requirements for the registration of new drugs. Nonetheless this was important research that drew on the depth of expertise in pharmacology and chemistry among university researchers and a major Australian company with whom they collaborated and exchanged personnel.
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Burattini, Costanza, Giulia Battistini, Francesco Tamagnini, and Giorgio Aicardi. "Low-frequency stimulation evokes serotonin release in the nucleus accumbens and induces long-term depression via production of endocannabinoid." Journal of Neurophysiology 111, no. 5 (March 1, 2014): 1046–55. http://dx.doi.org/10.1152/jn.00498.2013.
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The nucleus accumbens (NAc), a major component of the mesolimbic system, is involved in the mediation of reinforcing and addictive properties of many dependence-producing drugs. Glutamatergic synapses within the NAc can express plasticity, including a form of endocannabinoid (eCB)-long-term depression (LTD). Recent evidences demonstrate cross talk between eCB signaling pathways and those of other receptor systems, including serotonin (5-HT); the extensive colocalization of CB1 and 5-HT receptors within the NAc suggests the potential for interplay between them. In the present study, we found that 20-min low-frequency (4 Hz) stimulation (LFS-4Hz) of glutamatergic afferences in rat brain slices induces a novel form of eCB-LTD in the NAc core, which requires 5-HT2 and CB1 receptor activation and L-type voltage-gated Ca2+ channel opening. Moreover, we found that exogenous 5-HT application (5 μM, 20 min) induces an analogous LTD (5-HT-LTD) at the same synapses, requiring the activation of the same receptors and the opening of the same Ca2+ channels; LFS-4Hz-LTD and 5-HT-LTD were mutually occlusive. Present results suggest that LFS-4Hz induces the release of 5-HT, which acts at 5-HT2 postsynaptic receptors, increasing Ca2+ influx through L-type voltage-gated channels and 2-arachidonoylglycerol production and release; the eCB travels retrogradely and binds to presynaptic CB1 receptors, causing a long-lasting decrease of glutamate release, resulting in LTD. These observations might be helpful to understand the neurophysiological mechanisms underlying drug addiction, major depression, and other psychiatric disorders characterized by dysfunction of 5-HT neurotransmission in the NAc.
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Takanashi, S., Y. Kaneko, and T. Takeuchi. "FRI0079 CHARACTERISTICS OF DIFFICULT-TO-TREAT RHEUMATOID ARTHRITIS." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 616.2–617. http://dx.doi.org/10.1136/annrheumdis-2020-eular.872.
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Background:Despite remarkable progress in therapy, not a few patients with rheumatoid arthritis (RA) have not achieved treatment target. Various factors can be ascribed to difficult-to-treat RA, however, little is known about their characteristics.Objectives:To clarify characteristics of patients with difficult-to-treat RA in real-world.Methods:We reviewed all consecutive RA patients in Keio University Hospital between 2016 and 2017 and collected medical information. We defined patients in moderate disease activity and high disease activity according to disease activity score for 28 joints (DAS28) at the last visit despite more than one year treatment for RA as difficult-to-treat RA and analyzed their clinical characteristics.Results:A total of 1693 patients with RA were enrolled in the analysis. The mean age at the last visit was 64 years old, female was 83%, and the mean disease duration was 11.9 years. Rheumatoid factor and anti-cyclic citrullinated peptide were positive for 76% and 75% of the patients, respectively. The current treatment were conventional synthetic disease modifying anti-rheumatic drugs in 73%, biologic agents or janus kinase (JAK) inhibitors in 57%, and glucocorticoids in 13%. Disease activity according to DAS28 was remission in 65%, low disease activity in 21%, and moderate/high disease activity in 14%, which was defined as difficult-to-treat RA. Characteristics of difficult-to-treat RA were the mean age of 70 years old, female of 89%, and the mean disease duration of 14.8 years. The current treatments were conventional synthetic disease modifying anti-rheumatic drugs alone in 40.7%, biologic agents or JAK inhibitors in 55.8%, and glucocorticoids in 29.0%. The causes of difficult-to-treat RA were unresponsiveness to several biologic agents and/or JAK inhibitors in 22.9%, comorbidities in 33.8%, and personal reasons in 39.8% (costs in 35.9%, low adherence in 4.3%, concerns about possible adverse reaction of drugs in 54.3% and high patient global assessment in 5.4%). Patient characteristics were significantly different between the causes; age at RA onset (51 vs 61 vs 51 years, p<0.001), current age (65 vs 77 vs 66 years, p<0.001), estimated glomerular filtration rate (75 vs 61 vs 73 mL/min/1.73m2, p<0.001), tender joint count (3.4 vs 1.6 vs 2.1, p=0.005), swollen joint count (3.1 vs 1.6 vs 2.9, p=0.003), evaluator global assessment (21 vs 14 vs 16 mm, p=0.03), health assessment questionnaire-disability index (1.3 vs 1.3 vs 0.9, p=0.005), a history of serious infection (28 vs 41 vs 13%, p<0.001) and rheumatic disease comorbidity index (1.2 vs 2.2 vs 0.9, p<0.001).Conclusion:There are still 14% of patients with RA were difficult-to-treat in real world in spite of intensive treatment. Their characteristics are distinct by the cause of difficulty to treat, suggesting the approach to difficult-to-treat RA should be personalized.References:[1]Roodenrijs NMT, de Hair MJH, van der Goes MC et al. Characteristics of difficult-to-treat rheumatoid arthritis: results of an international survey. Ann Rheum Dis. 2018;77(12):1705-1709.[2]de Hair MJH, Jacobs JWG, Schoneveld JLM, van Laar JM. Difficult-to-treat rheumatoid arthritis: an area of unmet clinical need. Rheumatology (Oxford). 2017 Oct 4. doi: 10.1093/rheumatology/kex349.[3]England BR, Sayles H, Mikuls TR, Johnson DS, Michaud K. Validation of the rheumatic disease comorbidity index. Arthritis Care Res (Hoboken)2015;67(6):865–72.Disclosure of Interests:Satoshi Takanashi: None declared, Yuko Kaneko Speakers bureau: Dr. Kaneko reports personal fees from AbbVie, personal fees from Astellas, personal fees from Ayumi, personal fees from Bristol-Myers Squibb, personal fees from Chugai, personal fees from Eisai, personal fees from Eli Lilly, personal fees from Hisamitsu, personal fees from Jansen, personal fees from Kissei, personal fees from Pfizer, personal fees from Sanofi, personal fees from Takeda, personal fees from Tanabe-Mitsubishi, personal fees from UCB, Tsutomu Takeuchi Grant/research support from: Eisai Co., Ltd, Astellas Pharma Inc., AbbVie GK, Asahi Kasei Pharma Corporation, Nippon Kayaku Co., Ltd, Takeda Pharmaceutical Company Ltd, UCB Pharma, Shionogi & Co., Ltd., Mitsubishi-Tanabe Pharma Corp., Daiichi Sankyo Co., Ltd., Chugai Pharmaceutical Co. Ltd., Consultant of: Chugai Pharmaceutical Co Ltd, Astellas Pharma Inc., Eli Lilly Japan KK, Speakers bureau: AbbVie GK, Eisai Co., Ltd, Mitsubishi-Tanabe Pharma Corporation, Chugai Pharmaceutical Co Ltd, Bristol-Myers Squibb Company, AYUMI Pharmaceutical Corp., Eisai Co., Ltd, Daiichi Sankyo Co., Ltd., Gilead Sciences, Inc., Novartis Pharma K.K., Pfizer Japan Inc., Sanofi K.K., Dainippon Sumitomo Co., Ltd.
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Cuddihy, Andrew R., Parisa Asvadi, Rosanne Dunn, Tiffany T. Khong, and Andrew Spencer. "The Anti-Kappa Monoclonal Antibody MDX-1097 Synergizes with Immunomodulatory Drugs to Enhance Antibody-Dependent Cell Cytotoxicity of Multiple Myeloma Cells." Blood 120, no. 21 (November 16, 2012): 4012. http://dx.doi.org/10.1182/blood.v120.21.4012.4012.
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Abstract Abstract 4012 Multiple Myeloma (MM) is a cancer caused by the proliferation of malignant clonal plasma cells in the bone marrow and accounts for 10% of all hematologic malignancies. Recent advances have been made in the treatment and management of MM, however, despite these advances the majority of patients will ultimately relapse and die from their disease within 3–5 years from diagnosis. Several novel therapeutic approaches, including the use of antibody-based therapies, are being investigated to further improve the treatment of MM. MDX-1097 is a chimeric monoclonal antibody being assessed as a single agent in a Phase 2 clinical trial for the treatment of kappa light-chain restricted (κ-type) MM. MDX-1097 binds to the kappa myeloma antigen (KMA), a tumor-specific membrane-associated protein expressed on malignant plasma cells from patients with K-type MM. Previously we have demonstrated that MDX-1097 exerts its anti-tumour effects through multiple mechanisms, including antibody-dependent cell cytotoxicity (ADCC) in the presence of either normal human peripheral blood mononuclear cells (PBMCs) or purified natural killer (NK cells). The immunomodulatory drugs (IMiDs) lenalidomide (Revlimid) and pomalidomide (Actimid) are currently in use or being assessed for the treatment of MM. These IMiDs have been shown to exert their anti-tumor effects both directly, via apoptotic mechanisms, and indirectly via a number of different mechanisms including the augmentation of NK-dependent cellular cytotoxicity. In this study we report that IMiDs and MDX-1097 co-operate to promote enhanced ADCC of MM cells. In vitro treatment of normal PBMCs with IMiDs led to a 1.4-fold higher level of ADCC-mediated cell death of MDX-1097 spiked JJN3 cells (a κ-type MM cell line) compared with vehicle-treated PBMCs from the same donor. Similarly, in vivo lenalidomide exposed PBMCs isolated from a MM patient were, on average, 1.8-fold more effective in killing MDX-1097 spiked JJN3 cells in vitro compared to PBMC obtained from the same patient prior to lenalidomide treatment. Treatment of JJN3 cells with IMiDs resulted in significantly increased cell surface expression of KMA (lenalidomide: 1.9-fold, p < 0.001; pomalidomide: 2.3-fold, p < 0.01). These IMiD-treated JJN3 cells, when spiked with MDX-1097 were 1.7-fold more susceptible to ADCC-mediated cell death in the presence of untreated PBMCs, compared to JJN3 cells treated with vehicle alone. This difference in sensitivity to ADCC mediated cell death is presumably due to increased KMA expression resulting in more binding sites for MDX-1097, therefore facilitating recruitment of PB immune effector cells. Furthermore, combining IMiD-treated PBMCs with IMiD-treated, MDX-1097 spiked JJN3 cells resulted in a further increment in ADCC-mediated JJN3 cell death. This study demonstrates that in vivo and in vitro treatment of PBMCs with IMiDs engages the PB immune effector cells, leading to increased ADCC-induced κ-type MM cell death in vitro in the presence of MDX-1097. IMiDs also increase cell surface expression of KMA, leading to increased MDX-1097 binding and in turn also enhancing ADCC-induced MM cell killing. Our data provides a rationale for the clinical evaluation of a combination therapy involving both IMiDs and MDX-1097 for the treatment of k-type MM. Disclosures: Cuddihy: Immune System Therapeutics Ltd: Research Funding. Asvadi:Immune System Therapeutics Ltd: Employment. Dunn:Immune System Therapeutics Ltd: Employment, Equity Ownership. Spencer:Immune System Therapeutics Ltd: Research Funding.
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Morishita, Takanobu, Fumihiko Hayakawa, Keiki Sugimoto, Daiki Hirano, Yuki Kojima, Naoto Imoto, Yuichiro Inagaki, Tomoki Naoe, and Hitoshi Kiyoi. "A Photosensitizer Verteporfin Has Light-Independent Anti-Leukemic Activity for Ph-Positive Acute Lymphoblastic Leukemia and Synergistically Works with Dasatinib in Vivo." Blood 126, no. 23 (December 3, 2015): 1331. http://dx.doi.org/10.1182/blood.v126.23.1331.1331.
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Abstract Despite of great improvement of treatment outcome by ABL kinase inhibitors, Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is still intractable disease, and novel therapeutic agents are anticipated. We recently developed a high-throughput drug screening system using patient-derived xenograft (PDX) cells. PDX cells highly maintain phenotypes of primary malignant cells, such as heterogeneity of cancer cells, slower growth rate than cell lines, and microenvironment dependency. Drug screening by PDX cells can pick up anti-tumor reagents with new mechanisms that were overlooked by conventional cell-line based screenings. Here, we discovered verteporfin, an approved drug for macular degeneration, as a candidate for novel therapeutic agent of Ph+ ALL. We established PDX of 3 Ph+ ALL patients (PhLO, PhLK, and PhLH) by transplanting primary Ph+ ALL cells into NOD/SCID/IL-2Rgnull (NOG) mice. We developed a high-throughput drug screening system using one of these PDX cells (PDX screening) and screened the library of 3440 compounds containing approved drugs and pharmacologically active reagents. The profile of drugs selected by PDX screening was quite different from that by the screening using Ph+ ALL cell line (Cell line screening). Verteporfin was selected by PDX screening, whereas it did not demonstrate very high anti-leukemic effect in Cell line screening. We confirmed the anti-leukemic effect of verteporfin ex vivo using the 3 PDX cells and ALL-1, the cell line used in the Cell line screening. All 3 PDX cells were more sensitive to verteporfin than ALL-1 (EC50: PhLO cells, 228 nM; PhLK cells, 1.8 µM; PhLH cells; 395 nM; ALL-1, 3.93 µM). In addition, combined use of verteporfin and dasatinib, an ABL kinase inhibitor used for the treatment of Ph+ ALL, showed synergistic growth suppression of PhLO cells. Combination index (CI) values calculated by combination index algorism were less than 1.0 in most combinations of 16 data points (CI mean, 0.73; CI range, 0.28-1.34). Furthermore, the mechanism of action of verteporfin was intensively investigated. In combination with red light irradiation, verteporfin induces apoptosis of tumor cells through production of reactive oxygen species (ROS), which is known as photodynamic therapy. We revealed that verteporfin produced ROS light-independently in PhLO cells and induced their apoptosis. Verteporfin-induced apoptosis was inhibited by the addition of reduced glutathione to the culture medium, suggesting the large involvement of ROS production in the verteporfin-induced apoptosis. Finally, we assessed the in vivo effect of verteporfin. NOG mice transplanted with PhLO cells were treated with vehicle, verteporfin (140mg/kg/day), dasatinib (20mg/kg/day), or both of them from day 22 to day 28. Dasatinib was intraperitoneally injected and verteporfin was administered by continuous subcutaneous injection using osmotic pumps because of its very short half-life. We measured the ratios of leukemic PDX cells in bone marrow and spleen on day 28. Both single therapies by verteporfin and dasatinib significantly reduced the leukemia cell ratios in spleen and the combination therapy of them further reduced leukemia cells in spleen (Figure A). In bone marrow, both single therapies demonstrated weaker anti-leukemic effect than in spleen, but the combination therapy showed significantly enhanced effect, indicating the synergistic effect between them in vivo (Figure B). These results indicate the promisingness of verteporfin as a new anti-leukemic reagent and PDX screening as a new strategy for the development of anti-cancer drug. Figure 1. Figure 1. Disclosures Naoe: Pfizer Inc.: Research Funding; Toyama Chemical Co.,LTD.: Research Funding; Otsuka Pharmaceutical Co.,Ltd.: Patents & Royalties, Research Funding; Nippon Boehringer Ingelheim Co., Ltd.: Research Funding; Kyowa-Hakko Kirin Co.,Ltd.: Patents & Royalties, Research Funding; Fujifilm Corporation: Patents & Royalties, Research Funding; Chugai Pharmaceutical Co.,LTD: Patents & Royalties; Celgene K.K.: Research Funding; Astellas Pharma Inc.: Research Funding. Kiyoi:Yakult Honsha Co.,Ltd.: Research Funding; Novartis Pharma K.K.: Research Funding; MSD K.K.: Research Funding; Eisai Co., Ltd.: Research Funding; Alexion Pharmaceuticals: Research Funding; FUJIFILM Corporation: Patents & Royalties, Research Funding; Nippon Boehringer Ingelheim Co., Ltd.: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; FUJIFILM RI Pharma Co.,Ltd.: Research Funding; Teijin Ltd.: Research Funding; Japan Blood Products Organization: Research Funding; Astellas Pharma Inc.: Consultancy, Research Funding; Taisho Toyama Pharmaceutical Co., Ltd.: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding; Pfizer Inc.: Research Funding; Mochida Pharmaceutical Co., Ltd.: Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding.
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Banjo, Toshihiro, Yasuhiro Hama, Emi Nosaka, Yoshimi Takata, Daisuke Honma, Mayumi Kitagawa, Yuka Yamamoto, et al. "EZH1/2 Dual Inhibitor Valemetostat Tosylate (DS-3201b) Acts Differently from EZH2 Selective Inhibitor on Epigenetic Landscape to Exert Greater Anti-Tumor Effect Against Diffuse Large B-Cell Lymphoma." Blood 138, Supplement 1 (November 5, 2021): 2948. http://dx.doi.org/10.1182/blood-2021-146772.
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Abstract Enhancer of zeste homologous (EZH) 2 and its close homolog EZH1 are catalytic subunits of polycomb repressive complex (PRC) 2 protein complex, and play redundant and crucial role for the maintenance of transcriptional repression by tri-methylating histone H3 lysine 27 (H3K27). Hyper trimethylation of H3K27 has been associated with malignant lymphoma and myeloma progression, thus several small molecules suppressing PRC2 complex activity has been developed for hematological malignancy therapy. We have developed valemetostat tosylate (DS-3201b, also known as valematostat), a potent dual inhibitor of EZH1/2, and demonstrated its superior anti-proliferative effect against DLBCL cells to tazemetostat (EPZ-6438, E7438) a selective EZH2 inhibitor currently in clinic. In addition, valemetostat synergized with wide variety of 1st and 2nd line drugs used in DLBCL therapy both in vitro and in vivo proposing its potential combination opportunities. However, it is still elusive how valemetostat modulates epigenetic landscape and represses malignant B-cell proliferation more potently than selective EZH2 inhibitors. Therefore, impact on epigenetic landscape between valemetostat and tazemetostat was analyzed by RNA/ChIP-sequencing. Though these two inhibitors significantly reduced cellular global H3K27me3 level, we observed ectopic EZH1/2 accumulation in several tumor suppressor gene loci after tazemetostat treatment resulting in partial reduction in H3K27me3 and de-repression of silenced gene expression. Meanwhile valemetostat treatment evidently triggered gene expression by depleting H3K27me3 and enhancing H3K27Ac mark without inducing ectopic enrichment of EZH1/2, suggesting that valemetostat has a distinct effect on genome wide distribution of EZH1/2 from tazemetostat. In conclusion, these results suggest that valemetostat has a capacity of averting ectopic relocation of EZH1/2 on tumor suppressor genes mainly induced by EZH2 specific inhibition and thereby exerts greater anti-B cell tumor effect than EZH2 preferential inhibitor. A phase 2 clinical study of valemetostat is now ongoing for patients with Relapse/Refractory B-cell Lymphoma [ClinicalTrials.gov Identifier: NCT04842877] Disclosures Banjo: Daiichi Sankyo Co., Ltd.: Current Employment. Hama: Daiichi Sankyo Co., Ltd.: Current Employment. Nosaka: Daiichi Sankyo Co., Ltd.: Current Employment. Takata: Daiichi Sankyo Co., Ltd.: Current Employment. Honma: Daiichi Sankyo Co., Ltd.: Current Employment. Kitagawa: Daiichi Sankyo Co., Ltd.: Current Employment. Yamamoto: Daiichi Sankyo RD Novare Co., Ltd.: Current Employment. Wada: Daiichi Sankyo RD Novare Co., Ltd.: Current Employment. Yoshida: Daiichi Sankyo RD Novare Co., Ltd.: Current Employment. Lim: Daiichi Sankyo RD Novare Co., Ltd.: Current Employment. Okamoto: Daiichi Sankyo RD Novare Co., Ltd.: Current Employment. Sato: Daiichi Sankyo RD Novare Co., Ltd.: Current Employment. Katayama: Daiichi Sankyo RD Novare Co., Ltd.: Current Employment. Sato: Daiichi Sankyo RD Novare Co., Ltd.: Current Employment. Goto: Daiichi Sankyo RD Novare Co., Ltd.: Current Employment. Abe: Daiichi Sankyo Co., Ltd.: Current Employment.
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Balitska, O., V. Zlahoda, Yu Hryhoruk, and O. Cordon. "The pharmacoepidemiological analysis of the influenza pharmacotherapy in Ukraine." Management, economy and quality assurance in pharmacy, no. 1(65) (March 15, 2021): 54–59. http://dx.doi.org/10.24959/uekj.21.3.
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Influenza and other acute respiratory viral infections (ARIs) are the most common among human diseases that require timely medical attention and treatment with the most effective drugs. The aim of the study is pharmacoepidemiological analysis of drugs for the treatment of influenza registered in Ukraine. Materials and methods of research. The study was based on data from the State Register of Medicines of Ukraine, information on the results of the epidemic season of influenza and acute respiratory infections of the Center for Public Health of the Ministry of Health of Ukraine, declared drugs under the International Nonproprietary or Common Name in Ukraine as of January 2021. Methods: retrospective, descriptive and frequency analyzes. Results and discussion. A pharmacoepidemiological analysis of influenza drugs in Ukraine was conducted. It was found that the incidence of influenza and SARS during the study period decreased by 3.1% of the total population. Fatalities due to influenza and SARS increased by 41 cases during the study period, which may be related to the coronavirus pandemic. According to the results of a marketing study of antiviral drugs, it was found that the largest share in the structure of registered trade names are interferons (11 trade names). Conclusions. The analysis of the market showed that among the antiviral drugs registered in Ukraine for the studied period the dominance of domestic drugs is noted - 54% (respectively of foreign origin - 46%). Analysis of the distribution of domestic analogues of antiviral drugs by manufacturers found that the largest (5 and 4 TN) belongs to LLC "Research and production company" Interpharmbiotek and FZ "Biopharma" Ltd., Ukraine, Bila Tserkva. Key words: influenza; pharmacoepidemiological analysis; antiviral drugs
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Watson, Roger. "Psychotropic Drugs and the Elderly: Fast Facts Joel Sadavoy Psychotropic Drugs and the Elderly: Fast Facts WW Norton & Company Ltd 749 pp £37 0 393 70375 4 0393703754." Nursing Older People 16, no. 6 (September 2004): 43. http://dx.doi.org/10.7748/nop.16.6.43.s22.
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Procter, Andrew. "Neurotransmitters, Drugs and Brain Function. Edited by R. A. Webster. John Wiley and Sons, Ltd, Chichester, 2001. Pages: 534. £100.00." International Journal of Geriatric Psychiatry 17, no. 11 (October 28, 2002): 1081–82. http://dx.doi.org/10.1002/gps.742.
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Liu, Shanxi, Yanfeng Xiao, Jun Lv, Qingbo Liu, Pengbo Li, Penghui Wang, Yiguo Liu, and Peggy (Pei-Hua) Lu. "Study on the Efficacy and Safety of Non-Factor Drugs Applied the Etiological Classification for Treatment of Hemophilia:a Multi-Centre, Prospective Single-Arm Clinical Trial." Blood 128, no. 22 (December 2, 2016): 4986. http://dx.doi.org/10.1182/blood.v128.22.4986.4986.
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Abstract Objective: Research on the efficacy and safety of non-factor drugs applied the etiological classification for treatment of hemophilia. Diagnostic Methods: Between from June 2013 and June 2014, 73 patients were treated because of hemophilia. There were 69 males and 4 females, ages ranging from 0.4 to 83 years, with a mean of 16.13. We used MC-1000 Coagulometer (from MDC,Berlin, Germany) to detect the level of F¢ø/F¢ù:C, and detected the level of F¢ø/F¢ù inhibitor using Nigmegen assay. To detect mutations in the F8 and F9 gene, Intron 22 inversions were studied by inverse-shifting polymerase chain reaction (IS-PCR) and intron 1 inversions by long distance polymerase chain reaction. Point mutations were studied by sequencing the coding and promoter regions of the F8 and F9 genes. Therapeutic Methods: Patients with hemophilia were prospectively treated with Non-factor drugs without replacement therapy of F¢ø/F¢ù factor. Patients with mutations in f8 and f9 genes were treated with orally Compound Hemophilia Capsule (Shaanxi Yida Hemophilia Institute, Pat. No:ZL201410130047X, Shaanxi Drug Approval No.Z20150044). Each capsules contain the traditional Chinese medicine raw materials as shown in the following: Ginseng Radix et Rhizoma 0.035g, Astragali Radix 0.117g, Angelica Sinensis Radix 0.035g, Paeoniae Radix Alba 0.07g, Ligustri Lucidi Fructus 0.058g, Ecliptae Herba 0.058g etc. specification: 0.3g/capsule*40 capsule/bollte. The effect of drugs was to enhance the activity and synthesis of coagulation factors in hepatocyte. The dose of 1.2g for adults administered three times daily from 3 months to 6 months. The LD50 of the drugs is 32g/Kg in the mice's acute toxicity test, which is equivalently to 533 times than the therapeutic dosage. In this study, no acute toxicity were observed. Other patients with normal f8 and f9 genes were treated with three kinds of drugs as shown in the following: Cyclophosphamide Injection (Shanxi Pude Pharmaceutical Co., Ltd, Shanxi province, China, H14023686). The dose of 0.2g for adults administered four-intravenous-drip daily from 4 weeks to 6 weeks. Compound Glycyrthizin Injection (Minophagen Pharmaceutical Co.,Ltd, Eisai China Inc. H20190124). The dose of 0.04g for adults administered four-intravenous-drip daily for 4 weeks. The effect of drugs was to stimulating the proliferation and protecting hepatocyte. Mycophemolate Mofetil Capsule (Cisen Pharmaceutical Co., Ltd. Shandong province. China, H20080764). The dose of 1.0g for adults administered twice daily by oral. The effect of drugs was immunosuppressive. Results: Patients were classified by HA (52 cases, 71.23%, F¢ø:C in 1.94±1.59%) and HB (21 cases, 28.77%, F¢ù:C in 2.13±2.06%). There were 58 patients (79.45%) who were detected mutations with maternally inherited, 5 patients(6.85%) who detected mutations without maternally inherited, and 10 cases(13.70%) who had normal f8 and f9 genes. 20 days later after treatment, the level of F¢ø:C was raised from 1.94±1.59 to 11.85±41.33%(P£¼0.01), and the level of F¢ù:C was raised from 2.13±2.06% to 10.10±19.97%(P£¼0.01). However, the patients with normal f8 and f9 genes had the better curative effects (The results were shown in Table/ Figure). After one year, the level of F¢ø:C was 38.89±63.47% in 21 patients with HA, and the level of F¢ù:C was 17.60±32.16% in 10 patients with HB. None of patients reported adverse effects in clinical trials. Conclusion: Non-factor drugs for treatment of hemophilia could promoted the level of F¢ø/F¢ù:C in varying degrees and reduced symptoms. Therefore, the study could provide a new insight into treatment of hemophilia. Further research was needed to understand the mechanism and curative effect. The Institutional Ethics Committee approved the study (Approval No: 20120319). Registration ID: WHO ICTRP & ChiCTR-OPC-16008561 Disclosures No relevant conflicts of interest to declare.
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Sakai, R., E. Tanaka, M. Majima, and M. Harigai. "FRI0075 DECREASED RISKS OF HOSPITALIZED INFECTION UNDER TARGETED THERAPIES VS METHOTREXATE IN ELDERLY AND OLDER ELDERLY PATIENTS COMPARED TO YOUNGER PATIENTS WITH RHEUMATOID ARTHRITIS USING JAPANESE HEALTH INSURANCE DATABASE." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 614–15. http://dx.doi.org/10.1136/annrheumdis-2020-eular.1913.
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Background:Recently, vital prognosis has been improved in patients with rheumatoid arthritis (RA)1. In elderly patients, it is difficult to establish a treatment strategy due to multi-morbidities and treatment-related risks. Since older age is a significant risk factor of serious infections, one of the primary concerns during treatment of RA, rheumatologists should always strike a balance between efficacy and safety of the immunosuppressive treatment. However, infection data under the targeted therapy (TT) in elderly patients is still limited to date.Objectives:To compare the risk of hospitalized infection (HI) under the TT among young, elderly, and older elderly patients with RA using the Japanese health insurance database.Methods:This retrospective longitudinal population-based study was conducted using claims data in Japan provided by Medical Data Vision Co., Ltd. We defined individuals as RA cases if they met all of the following: 1) having at least one ICD10 code (M05x, M06x except for M061, or M08x except for M081 and M082); 2) having at least one prescription of disease-modifying antirheumatic drugs (DMARDs) including methotrexate (MTX) and TT (biological DMARDs and Janus kinase inhibitors) between April 2008 and September 2018; and 3) 16 years old or older. We define the month patients met the above all criteria for the first time in this database as the index month. We excluded patients who were prescribed any DMARDs during the first 12 months from MTX users and those with prescription of any TT during the first 12 months from TT users (i.e., prevalent users). Among the study population, we divided patients into 3 groups according to their age at the index month; young group (16-64), elderly group (65-74), and older elderly group (>=75). The observation started from the index month and ended at 36 months later, the last month of the exposure of DMARDs, the month of loss of follow-up, or September 2019, whichever came first. HI was defined by ICD10 code with one prescription of predefined drugs for each infection during hospitalizations. Some of HIs were defined by ICD10 code alone.Results:In this study, 8269, 6454, 5745 patients with RA were included in the young, elderly, and older elderly groups, respectively. The incidence rate (IR) of HI (/100 patient-years [PY]) [95%CI] was 3.4 [3.1-3.7] in the young group, 5.8 [5.3-6.3] in the elderly group, and 12.0 [11.2-12.8] in the older elderly group. IR rate (IRR) of HI (reference: the young group) was 1.7 [1.5-1.9] in the elderly group and 3.6 [3.2-4.0] in the older elderly group. In the young group, the IRR of HI in TT users vs MTX users was significantly elevated (1.8 [1.5-2.1]), whereas, those of the elderly and the older elderly groups were significantly decreased (IRR 0.8 [0.7-0.9] for elderly; 0.6 [0.5-0.7] for older elderly). Concomitant use of immunosuppressive DMARDs or prednisolone >=10mg/day with TT became less frequent with aging.Conclusion:The elderly and older elderly patients had significantly higher risks of HI compared to the young. The risk of HI under the TT compared to MTX was decreased in the elderly patients, probably due to adjusting for treatment by attending physicians.References:[1]Arthritis Rheum 2014;66:786-93Acknowledgments:This work was supported by JSPS KAKENHI Grant Number 17K08963.Disclosure of Interests:Ryoko Sakai Grant/research support from: Tokyo Women’s Medical University (TWMU) has received unrestricted research grants forDivision of Epidemiology and Pharmacoepidemiology of Rheumatic Diseases from Ayumi Pharmaceutical Co. Ltd., Bristol Meyers Squib, Chugai Pharmaceutical Co. Ltd., Nippon Kayaku Co. Ltd., Taisho Toyama Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Corp., and with which TWMU paid the salary of R.S., Eiichi Tanaka Consultant of: ET has received lecture fees or consulting fees from Abbvie, Asahi Kasei pharma co., Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo Co., Eisai Pharmaceutical, Janssen Pharmaceutical K.K., Nippon Kayaku, Pfizer, Takeda Pharmaceutical, Taisho Toyama Pharmaceutical Co., and UCB Pharma., Speakers bureau: ET has received lecture fees or consulting fees from Abbvie, Asahi Kasei pharma co., Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo Co., Eisai Pharmaceutical, Janssen Pharmaceutical K.K., Nippon Kayaku, Pfizer, Takeda Pharmaceutical, Taisho Toyama Pharmaceutical Co., and UCB Pharma., masako majima: None declared, masayoshi harigai Grant/research support from: AbbVie Japan GK, Ayumi Pharmaceutical Co., Bristol Myers Squibb Co., Ltd., Eisai Co., Ltd., Mitsubishi Tanabe Pharma Co., Nippon Kayaku Co., Ltd., and Teijin Pharma Ltd. MH has received speaker’s fee from AbbVie Japan GK, Ayumi Pharmaceutical Co., Boehringer Ingelheim Japan, Inc., Bristol Myers Squibb Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., GlaxoSmithKline K.K., Kissei Pharmaceutical Co., Ltd., Oxford Immuotec, Pfizer Japan Inc., and Teijin Pharma Ltd. MH is a consultant for AbbVie, Boehringer-ingelheim, Kissei Pharmaceutical Co., Ltd. and Teijin Pharma.
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Tremblay, Johane. "Décisions rendues par le Conseil canadien des relations du travail." Relations industrielles 42, no. 4 (April 12, 2005): 852–61. http://dx.doi.org/10.7202/050367ar.
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Au cours des derniers mois, le Conseil a rendu deux décisions importantes dans le secteur des postes. Le 29 avril, le Conseil reconnaissait aux facteurs ruraux le statut d'employé au sens du paragraphe 107(1) du Code canadien du travail, alors que le 1er septembre, il concluait qu'une vente d'entreprise était survenue par suite d'un contrat de franchise conclu entre la Société canadienne des postes et Sheldon Manly Drugs Ltd. Ces deux décisions qui font encore les manchettes seront résumées dans la présente chronique.
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Anno, S., T. Okano, K. Inui, T. Koike, and H. Nakamura. "AB0235 DENOSUMAB INCREASE THE BONE MINERAL DENSITY REGARDLESS OF DISEASE ACTIVITY, THE BIOLOGICAL DISEASE-MODIFYING ANTIRHEUMATIC DRUGS, THE CONCOMITANT TYPE OF VITAMIN D, AND PRETREATMENT OF OSTEOPOROSIS IN PATIENTS WITH RHEUMATOID ARTHRITIS." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 1417.2–1418. http://dx.doi.org/10.1136/annrheumdis-2020-eular.2538.
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Background:Osteoporosis is one of the major comorbidities in patients with rheumatoid arthritis (RA). There are a lot of evidence that denosumab increase bone mineral density (BMD) in patients with osteoporosis. However, there are few reports investigated the influence of denosumab in patients with RA.Objectives:We evaluated the BMD change in patients with RA treated denosumab and assessed the effect of various factors, such as disease activity, biological disease-modifying anti-rheumatic drugs (bDMARDs) use, concomitant medications of osteoporosis and pretreatment of osteoporosis.Methods:This study included 140 consecutive RA patients (135 female, mean age was 70.6 ± 8.6 years) who fullfilled the criteria of osteoporosis and treated with denosumab. BMD at the lumbar spine, proximal femoral and femoral neck were evaluated by dual energy X-ray absorptiometry at baseline and one year after treatment. We evaluated the influence of disease activity, bDMARDs use, the concomitant type of vitamin D and pretreatment of osteoporosis for BMD change.Results:BMD change at the lumbar spine, proximal femoral and femoral neck were 5.9% (p<0.01), 4.0% (p<0.01), and 1.2% (p=0.36) durling one year. There were no differences in improvement ratio of BMD between each parameters (fig 1). Disease activity: 75 patients in remission or low disease activity and 65 patients in moderate or high disease activity were 6.4 vs 5.3% (p=0.91), 3.0 vs 5.1% (p=0.73), 2.0 vs 0.3% (p=0.1). bDMARDs: 45 patients with bDMARDs (anti-tumor necrosis factor inhibitors (TNF): 23, tocilizmab (TCZ): 13, abatacept (ABT): 7, Tofacitinib: 2) and 93 patients without bDMARDs were 6.0 vs 5.8% (p=0.31), 4.3 vs 4.1% (p=0.57), -0.2 vs 1.8% (p=0.18). Type of vitamin D: 47 patients taking active form vitamin D and 60 patients taking native form vitamin D were 5.5 vs 6.8% (p=0.82), 3.1 vs 3.8% (p=0.93), 0.4 vs 1.9% (p=0.14). Pretreatment of osteoporosis: 74 patients with pretreatment of osteoporosis (bisphosphonate:58, teriparatide:16) and 66 patients without pretreatment of osteoporosis were 6.9 vs 5.4% (p=0.41), 0.9 vs 4.0% (p=0.22), 2.0 vs 1.2% (p=0.68). Moreover, BMD change were not different in bDMARDs type, 5.0, 6.4, 0.5% in TNF group, 4.8, 0.7, -1.9% in TCZ group, 9.7, 4.9, 0.2% in ABT group (TNF vs TCZ: p=0.83, 0.98, 0.81, TNF vs ABT: p=0.83, 0.41, 0.97, TCZ vs ABT: p=0.98, 0.43, 0.9). There were no difference between bisphosphonate and teriparatide (6.2 vs 6.9%: p=0.49, 4.8 vs 0.9%: p=0.35, 0.9 vs 2.0%: p=0.49).Conclusion:Denosumab improved BMD in patients with RA independently regardless of disease activity, bDMARDs, the concomitant type of vitamin D and pretreatment of osteoporosis.References:[1]Y Nakamura et al, Arch Osteoporos: 2017; 12:80.[2]K Kaneko et al, Journal of Experimental Orthopaedics: 2019; 6:41.[3]T Suzuki et al, Therapeutics and Clinical Risk Management: 2018; 14:453–459.Acknowledgments:We wish to thank Atsuko Kamiyama, Tomoko Nakatsuka, Masato Uematsu and all participants in this study.Disclosure of Interests:Shohei Anno: None declared, Tadashi Okano Grant/research support from: AbbVie, Eisai, Mitsubishi Tanabe Pharma Corporation and Nipponkayaku, Speakers bureau: AbbVie, Asahikasei, Astellas Pharma Inc, Ayumi Pharmaceutical, Bristol-Myers Squibb, Chugai Pharmaceutical, Daiich Sankyo, Eisai, Janssen, Lilly, Mitsubishi Tanabe Pharma Corporation, Novartis Pharma, Ono Pharmaceutical, Pfizer, Sanofi, Takeda Pharmaceutical, Teijin Pharma and UCB, Kentaro Inui Grant/research support from: Janssen Pharmaceutical K.K., Astellas Pharma Inc., Sanofi K.K., Abbvie GK, Takeda Pharmaceutical Co. Ltd., QOL RD Co. Ltd., Mitsubishi Tanabe Pharma, Ono Pharmaceutical Co. Ltd., Eisai Co.,Ltd.,, Speakers bureau: Daiichi Sankyo Co. Ltd., Mitsubishi Tanabe Pharma, Janssen Pharmaceutical K.K., Astellas Pharma Inc., Takeda Pharmaceutical Co. Ltd., Ono Pharmaceutical Co. Ltd., Abbvie GK, Pfizer Inc., Eisai Co.,Ltd., Chugai Pharmaceutical Co., Ltd., Tatsuya Koike Grant/research support from: AbbVie, Astellas Pharma Inc, Bristol-Myers Squibb, Chugai Pharmaceutical, Eisai, Janssen, Lilly, Mitsubishi Tanabe Pharma Corporation, MSD, Ono Pharmaceutical, Pfizer, Roche, Takeda Pharmaceutical, Teijin Pharma, and UCB, Speakers bureau: AbbVie, Astellas Pharma Inc, Bristol-Myers Squibb, Chugai Pharmaceutical, Eisai, Janssen, Lilly, Mitsubishi Tanabe Pharma Corporation, MSD, Ono Pharmaceutical, Pfizer, Roche, Takeda Pharmaceutical, Teijin Pharma, and UCB, Hiroaki Nakamura Grant/research support from: Astellas Pharma Inc. and Asahi Kasei Pharma Co.
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Garg, Amit, Anupama R. Singh, Shyamal S. Kadukkatt, Juan Pablo, and Shyam Akku. "Generic dRug Adoption Framework: Framework to assess perceptions and identify high-quality generic drugs in oncology." Journal of Generic Medicines: The Business Journal for the Generic Medicines Sector 15, no. 2 (June 2019): 69–75. http://dx.doi.org/10.1177/1741134319833122.
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Perceptions in physicians and pharmacists are a common impediment to the utilization of generic medicines in clinical practice. As a multinational initiative to accelerate access to high-quality generic medicines, Dr Reddy’s Laboratories Ltd has developed the Generic dRug Adoption Framework. Currently available in four languages (English, Portuguese, Spanish, and Russian) and four (Malaysia, Brazil, Colombia, and Ukraine) countries, the framework will enable physicians and pharmacists to identify high-quality generics and help towards switching from originator to generic medicines. This can help to increase the adoption and access for generic medicines. The platform is not intended to guide treatment decisions but can help healthcare providers to differentiate a high-quality generic medicine based on parameters of effectiveness, safety, quality, and costs.
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Agrawal, M. Y., Y. P. Agrawal, A. Pedhavi, G. Hanmante, and K. Sharma. "A Survey on Oral Antidiabetic Drugs available in Market for Non-complicated Diabetic Patients within Ratnagiri Region." International Journal of PharmTech Research 13, no. 4 (2020): 399–409. http://dx.doi.org/10.20902/ijptr.2019.130413.
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Background: This survey was designed to analyze the current oral anti-diabetic drugs prescribed for non-complicated diabetic patients within Ratnagiri region on the basis of variation in prices of same drug available in different brands. Methods: The present survey has been conducted for a period of 4 months involving number of medical stores in Ratnagiri, Maharashtra, Doctors and Patients with randomly evaluating around 650 prescriptions. A standard questionnaire was prepared containing different questions; based on patient’s data (such as age, gender, disease history and medications), Doctor’s data (commonly prescribed drug, combination) and chemist data (available alternatives, cost and most selling brands). Results: Statistical analysis of patients data revels that there were 47.5% patients are in between the ages of 50 to 60 years and 92.5 % patient depends on oral antidiabetic drugs. Hypertension was the most common complication found among them (54%). Data from Doctor’s during survey suggested Metformin as mostly prescribed drug to patients having type- II Diabetes Mellitus as a single entity or in fixed dose combinations with Glimiperide or Gliclazide. An exhaustive survey over medical shops revealed that many brands of Metformin and Metformin in combination with Glimiperide or Gliclazide are available in market, but Glycomate (Metformin), Glycomate GP-1 (Metformin and Glimiperide) and Glizid-M (Metformin and Gliclazide) is mostly prescribed by Doctors and sold by Chemist though their cheapest alternatives are available in market. Cost analysis indicates that, wide variation in price of several brands (75-87 %) for oral anti-diabetics. Annual Turnover of these products in Indian domestic market indicates dominance of USV Pvt. Ltd. and Mankind Ltd. over other Pharmaceutical companies. Conclusions: This report will create better awareness among people for the availability of various brands of same anti-diabetic drug and also motivate our physicians to prescribe the economic products.
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Sapova, K. I., and S. V. Ryazantsev. "Characteristics of the treatment of perennial allergic rhinitis in patients of the older age group." Medical Council, no. 20 (November 14, 2018): 107–10. http://dx.doi.org/10.21518/2079-701x-2018-20-107-110.
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Recent studies show that perennial allergic rhinitis is prevalent among older people, but the management of this disease is underestimated and not determined. This article describes the persistent allergic rhinitis in patients of the older age group and identifies the primary goals of treatment based on the age-related physiological factors, concomitant conditions and the use of other drugs. Special attention is paid to the various options for the drug therapy in elderly patients over the age of 60 years. The second-generation antihistamines and intranasal glucocorticosteroids also have primacy over other drugs, when supervising older patients. A randomized open multicenter clinical study showed that Momate Rhino Advance (a combination of intranasal antihistamines (azelastine) and intranasal glucocorticosteroids (mometasone) for the treatment of allergic rhinitis) made by Indian Glenmark Pharmaceuticals Ltd. is effective and safe in patients aged 60 years and older, who are diagnosed with the above disease.
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Radcliffe, Polly. "Book Review: Angus Bancroft Drugs, Intoxication and Society Chichester: John Wiley and Sons Ltd., 2008, £15.99 pbk, (ISBN: 9780754635460), xii+220pp." Sociology 44, no. 6 (December 2010): 1215–17. http://dx.doi.org/10.1177/00380385100440061207.
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Goto, Emi, Akihiro Tomita, Akihide Atsumi, Hitoshi Kiyoi, and Tomoki Naoe. "Double Genetic Mutations in PML-Rara Fusion Gene Confirmed in a Patient Showing Resistance to All-Trans Retinoic Acid and Arsenic-Trioxide Therapy." Blood 114, no. 22 (November 20, 2009): 1743. http://dx.doi.org/10.1182/blood.v114.22.1743.1743.
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Abstract Abstract 1743 Poster Board I-769 Background Molecular targeting drugs, all-trans retinoic acid (ATRA)and arsenic trioxide (ATO), have major advances in the treatment of acute promyelocytic leukemia (APL). However, resistance to these drugs has been also observed in clinical practice. ATRA acts as a ligand for retinoic acid receptor alpha (RAR) and restores the aberrant transcription repression by PML-RARA fusion protein in APL cells. Previous reports demonstrate that amino-acids substitution, resulting from genetic mutations, in ligand binding domain (LBD) of RARA region of PML-RARA were closely related to drug resistance to ATRA therapy. In contrast, for ATO therapy, the molecular mechanisms of the effectiveness and also the resistance are still unclear. Here we identified a PML-RARA that holds double genetic missense mutations in RARA and PML regions, respectively, from an APL patient, who showed clinically resistance to ATRA and ATO therapy. These mutations were observed as his disease progression, and we are interested in the relationship between these mutations with drug resistance to ATRA and/or ATO. Aims Analyses of the molecular and clinical significance of the double missense mutations of PML-RARA for disease progression and resistance to ATRA and ATO therapy. Results Eight APL patients were treated with ATO in Nagoya University Hospital, Japan, during ∼5 years from Apr. 1, 2000 to Dec. 31, 2004. One out of 8 patients showed clinically ATO resistance. The patient showing ATO resistance firstly diagnosed as APL (M3 variant) from cytogenetic and chromosomal analyses, and complete remission was obtained after combination chemotherapy with ATRA. Molecular CR was confirmed by RT-PCR analysis, but after 3 month from the induction therapy, ATRA-resistant relapse was observed. After treatment with ATO therapy, response was observed, but the effectiveness was gradually decreased, resulting finally into the resistance. The patient died of disease progression. During his 7 years clinical course, leukemia cells were harvested repeatedly from his bone marrow and peripheral blood. RT-PCR using the total RNA from his tumor cells followed by DNA sequencing was performed, with the result of PML-RARA fusion gene with the bcr3 breakpoint in the intron 3 of PML. When using the tumor cells that were harvested at his terminal stage, a missense point mutation in the LBD of the RARA region of PML-RARA was confirmed. Furthermore, missense point mutation in the PML-B2 domain was also confirmed in the same cDNA clones. Interestingly, these mutations were not observed in the leukemia cells obtained at the onset. These mutations were analyzed in each sample that was obtained as his disease progressed, and some correlation between disease progression and/or the drug resistance and the timing of appearance of these two mutations were suggested. These mutated fusion transcripts were cloned into expression vectors, and we are now analyzing the function relating to the drug resistance and disease progression. Conclusions Double genetic missense mutations in the RARA-LBD and PML-B2 of PML-RARA were confirmed in ATRA and ATO resistant patient. These genetic mutations were confirmed in the leukemia cells during his disease progression, and the relationship between those mutations and drug resistances were suggested from the clinical features. Mutations in the PML-B2 domain has not been reported previously, thus, it may be important to show whether this type of mutations are related to the drug resistance, especially to ATO therapy. Disclosures Kiyoi: Novartis Pharma Co. Ltd.: Research Funding; Kyowa Hakko Kirin Co. Ltd.: Consultancy. Naoe:Kyowa Hakko Kirin Co., Ltd. : Research Funding; Chugai Pharmaceutical Co.,Ltd.: Research Funding; Wyeth K.K.: Research Funding.
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Rahman, Md Shahinur, Subrata Mondal, and Amir Hossain. "Agrochemicals used in freshwater aquaculture in Jhenaidah district, Bangladesh." Asian-Australasian Journal of Food Safety and Security 3, no. 2 (November 30, 2019): 63–76. http://dx.doi.org/10.3329/aajfss.v3i2.55931.
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The present experiment was conducted in order to investigate the use of agrochemicals in freshwater aquaculture with emphasis on fish health management. The selected area was Mahespur upazila under Jhenaidah district and the study duration was six months. The main group was fifty fish farmers and the data were collected through interview with fish farmers and key informants (chemical seller). Ten categories of chemicals were identified that are used by fish farmers for various purposes such as pond preparation, water quality management, controlling diseases, supplying oxygen, killing fish predators, Ten pharmaceutical companies were found to provide the agrochemicals to fulfill the farmers need. These companies are Novartis Anmal Health Ltd, Fishtech (BD) Ltd, SK+F BD Ltd, Renata Ltd, ACI Animal Health, Opsonin Pharma Ltd, Eon Animal Health Products Ltd, Square Pharmaceuticals Ltd, Sciencetech Agro Industries Ltd, Rals. In the study area some kinds of diseases were founded such as Epizotic Ulcerative Syndrome (EUS) in Rohu (Labeo rohita), Catla (Catla catla), Mozambique tilapia (Oreochromis niloticus), Black spot in Stinging cat fish, skin diseases, gill damage, tail and fin rot in Yellow tail catfish (Pangasius pangasius). For highest stocking density tilapia and pangus were mostly affected by diseases in winter. Farmers use various chemicals such as for water quality management agriculture lime, Geotox, JV Zeolite, Mega Zeo Bio, Aquakleen and Biomin, as antibiotic they use Novamix 101, Erocot, Captor, Oxysentin 20%, Renamycin, Aquamycin and Oxysentin 20% are antibiotics with different trade names were seen in the market as well as used by the fish farmers in the study area. The fish farmers use a wide variety of disinfectants in freshwater aquaculture. Timsen, Polgard plus, Formalin, Bleaching powder, EDTA are found available in all the shops of Mahespur. Formalin is used to control protozoan diseases. Virex is used to destroy virus and bacteria. Fish farmers use oxygen suppliers to increase the oxygen level in the water body. Oxidizing agent, hydrogen peroxide are major active ingredients of such chemical. The recovery of fish diseases was found 80-90% in the study area. During field observation many problems were identified in case of using agrochemicals which included lack of skill and knowledge of farmers about the application, withdrawal period of agrochemicals and drugs and some adverse effects on fish and human health.
Asian Australas. J. Food Saf. Secur. 2019, 3(2), 63-76
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Miyamae, T., Y. Manabe, T. Sugihara, N. Umezawa, H. Yoshifuji, N. Tamura, Y. Abe, et al. "POS0794 PREGNANCY AND CHILDBIRTH IN TAKAYASU ARTERITIS IN JAPAN – A NATIONWIDE RETROSPECTIVE STUDY." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 684–85. http://dx.doi.org/10.1136/annrheumdis-2022-eular.980.
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BackgroundTakayasu arteritis (TAK), a granulomatous large vessel vasculitis, mainly involves the aorta and its proximal branches and commonly occurs in young females. However, studies of pregnancy in women with TAK are sparse and limited, probably due to the rarity of the disease.ObjectivesThe purpose of this study was to understand the status quo of medical treatments of the primary disease and outcomes of pregnancy in patients with TAK, and birth outcomes of the children in Japan.MethodsPatients with TAK who conceived after the onset of the disease and were managed at medical facilities participating in the Japan Research Committee of the Ministry of Health, Labour, and Welfare for Intractable Vasculitis (JPVAS) were retrospectively enrolled in this study. The following information was collected from patients who had a live-born baby: age at diagnosis of TAK, disease classification, age at delivery, treatments before and during pregnancy, complications during pregnancy, birth outcomes of the children, and changes in disease activity during pregnancy and after delivery.ResultsFifty-one cases and 69 pregnancies from 19 ethics committee-approved centers were enrolled during the study period 2019–2021. Of these, 49 cases and 66 pregnancies (95.7%) resulted in delivery and live-born babies. The Numano classification of the 49 cases was as follows: type I, 11; type IIa, 15; type IIb,12; type III, 1; type IV, 1; type V, 9; with type IIa being the most common. The age of diagnosis was 22 years (13–37 years, year of diagnosis 1965–2017), the median age of the delivery of 66 pregnancies was 31 years (year of delivery 1969-2021), and the median duration of illness at delivery was nine years. There were 34 planned pregnancies (51.5%, including four pregnancies by artificial insemination/ovulation induction). Preconception therapy included prednisolone (PSL) in 51 pregnancies (77.3%, median dose 7.5 mg (range 4–30 mg)/day), immunosuppressive drugs in 18 pregnancies (27.3%, azathioprine 8, tacrolimus 7, methotrexate 4, cyclosporin A 1, and colchicine 1), biologics in 12 pregnancies (18.1%, infliximab 6, tocilizumab 5, and adalimumab 1), antihypertensive drugs in 5 pregnancies (7.6%). Surgical treatment had been performed before pregnancy in 6 cases (aortic root replacement 2, subclavian artery dilatation 1, subclavian artery bypass 1, subclavian artery stenting 1, and ascending aorta semicircular artery replacement 1). Medications used during the course of pregnancy included PSL in 48 pregnancies (72.7%, median dose 8 mg (range 4–30 mg)/day, increased in 13 pregnancies, decreased in 1 pregnancy), immunosuppressants in 13 pregnancies (19.7%, azathioprine 6, tacrolimus 6, and cyclosporin A 1), biologics 9 pregnancies (13.6%, infliximab 4, tocilizumab 4, and adalimumab 1). Immunosuppressants and biologics were discontinued in five and four pregnancies after conception. Complications during pregnancy were observed in 20 pregnancies (30.3%), with hypertension being the most common. Complications related to TAK or its treatment were severe infections in two pregnancies and aneurysm enlargement due to increased circulating plasma volume in one pregnancy. Aortic arch replacement was performed after delivery for the latter case. Relapse of TAK was observed in 4 pregnancies (6.1%) during pregnancy and in 8 pregnancies (12.1%) after delivery. One pregnancy resulted in restenosis of subclavian artery for which dilatation procedure was performed prior to the pregnancy. There were 13/66 (19.7%) preterm infants and 17/59 (28.8%) low birth weight infants; all but one had a birth weight of more than 2,000 g and no had serious postnatal abnormalities. Forty-three (82.7%) of the 52 confirmed infants were breastfeed fully or mixed.ConclusionMost of the pregnancies in patients with TAK were successfully delivered while they had low disease activity at a dose of less than 10 mg/day of PSL. Relapse occurred during pregnancy and after delivery in some cases. The babies tended to have low birth weight, but 82.7% of them were breastfed without serious complications.Disclosure of InterestsTakako Miyamae: None declared, Yusuke Manabe: None declared, takahiko sugihara Speakers bureau: TS has received honoraria from Abbvie Japan Co., Ltd., AsahiKASEI Co., Ltd., Astellas Pharma Inc., Ayumi Pharmaceutical, Bristol Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Mitsubishi-Tanabe Pharma Co., Ono Pharmaceutical, Pfizer Japan Inc., Takeda Pharmaceutical Co. Ltd., and UCB Japan Co., Grant/research support from: TS has received research grants from AsahiKASEI Co., Ltd., Daiichi Sankyo., Chugai Pharmaceutical Co., Ltd., and Ono Pharmaceutical., Natsuka Umezawa: None declared, Hajime Yoshifuji Speakers bureau: HY has received lecture fees from Janssen and Chugai., Naoto Tamura: None declared, Yoshiyuki Abe: None declared, Shunsuke Furuta Speakers bureau: Chugai Pharmaceutical Co.,Ltd.DaiichiSankyo Co.,Ltd.Asahi-Kasei Pharma Corporation, Manami Kato: None declared, Takashi Kumagai: None declared, Kaito Nakamura: None declared, Hiroko Nagafuchi: None declared, Jun Ishizaki: None declared, Naoko Nakano: None declared, Tatsuya Atsumi Speakers bureau: Mitsubishi Tanabe Pharma Co., Chugai Pharmaceutical Co., Ltd., Astellas Pharma Inc., Takeda Pharmaceutical Co., Ltd., Pfizer Inc., AbbVie Inc., Eisai Co. Ltd., Daiichi Sankyo Co., Ltd., Bristol-Myers Squibb Co., UCB Japan Co. Ltd., Eli Lilly Japan K.K., Novartis Pharma K.K., Eli Lilly Japan K.K., Kyowa Kirin Co., Ltd.,TAIHO PHARMACEUTICAL CO., LTD., Consultant of: AstraZeneca plc., MEDICAL & BIOLOGICAL LABORATORIES CO., LTD., Pfizer Inc., AbbVie Inc., ONO PHARMACEUTICAL CO. LTD.,Novartis Pharma K.K., Nippon Boehringer Ingelheim Co., Ltd., Grant/research support from: Astellas Pharma Inc., TAIHO PHARMACEUTICAL CO., LTD.AbbVie Inc., Nippon Boehringer Ingelheim Co., Ltd.,Takeda Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co. Ltd., Otsuka Pharmaceutical Co., Ltd. and Pfizer Inc. Alexion Inc., TEIJIN PHARMA LIMITED., Kohei Karino: None declared, Koichi Amano Speakers bureau: AbbVie GK, Asahi-Kasei Pharma, Astellas, Chugai Pharmaceutical Co.Ltd., Eisai, Eli Lilly, GlaxoSmithKlein, Janssen Pharma, Pfizer Japan, Grant/research support from: Asahi-Kasei Pharma,Chugai Pharmaceutical Co.Ltd., Takahiko Kurasawa: None declared, Shuichi Ito: None declared, Ryusuke Yoshimi: None declared, Noriyoshi Ogawa: None declared, Shogo Banno: None declared, Taio Naniwa Speakers bureau: Chugai, Tanabe, Abbbvie, Eisai, Grant/research support from: Chugai, Tanabe, Abbbvie, Eisai, Satoshi Ito Speakers bureau: SI has received speaker’s fees from pharmaceutical companies., Akinori Hara: None declared, Shinya Hirahara: None declared, Haruhito A. Uchida: None declared, Yasuhiro Onishi: None declared, Yohko Murakawa Speakers bureau: Astellas, UCB, Chugai, AbbVie, Grant/research support from: Chugai, AbbVie, Yoshinori Komagata: None declared, Yoshikazu Nakaoka: None declared, Masayoshi Harigai Speakers bureau: MH has received speaker’s fee from AbbVie Japan GK, Ayumi Pharmaceutical Co., Boehringer Ingelheim Japan, Inc., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Janssen Pharmaceutical K.K., Kissei Pharmaceutical Co., Ltd., Novartis Japan, Pfizer Japan Inc., Mitsubishi Tanabe Pharma Co., Teijin Pharma Ltd and UCB Japan., Consultant of: MH is a consultant for AbbVie, Boehringer-Ingelheim, Kissei Pharmaceutical Co., Ltd., and Teijin Pharma.
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Kolganova, M. A., N. S. Bagaeva, YuV Medvedev, I. E. Shohin, A. V. Demchinskaya, T. N. Palkina, D. A. Salazanov, et al. "A Comparative Parallel Study of Pharmacokinetics and Immunogenicity Following Single Intravenous Administration of Bevacizumab Biosimilar RPH-001 (Manufactured by R-Pharm Group, Russia) and Avastin® (Manufactured by F. Hoffmann-La Roche Ltd., Switzerland) in Healthy Male Volunteers." Drug development & registration 8, no. 3 (September 5, 2019): 91–100. http://dx.doi.org/10.33380//2305-2066-2019-8-3-91-100.
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Introduction. Bevacizumab is a monoclonal IgG1 antibody that binds to and inhibits the biologic activity of human vascular endothelial growth factor (VEGF). Bevacizumab is used as a targeted mono- or combination therapy for different solid tumors. Phase I clinical trial was performed to assess pharmacokinetics (PK) and immunogenicity of bevacizumab drugs. For this study 80 healthy male volunteers were recruited and randomized to either Avastin or RPH-001 group.Aim. To assess and compare pharmacokinetics and immunogenicity (safety) following single intravenous administration of Avastin® (manufactured by F. Hoffmann-La Roche Ltd.,Switzerland) and bevacizumab biosimilar RPH-001 (manufactured by R-Pharm Group,Russia).Materials and methods. Bevacizumab quantitation and quasi-quantitative anti-bevacizumab antibodies detection in human blood serum were carried out using photometric ELISA. Two different methods were successfully validated.Results and discussion. Bevacizumab quantitation method was validated for selectivity and specificity, calibration curve, sensitivity, accuracy and precision, minimal required dilution, dilution linearity and stability. The anti-bevacizumab antibodies detection method was validated for cut-point (with normalization factor calculation), selectivity, sensitivity, precision, drug tolerance, dilution linearity, matrix effect (in case of serum hemolysis), and stability. The validated methods were successfully applied to pharmacokinetic and immunogenicity assessment of bevacizumab drugs. Conclusion. The results of the PK-study showed that test and reference bevacizumab drugs were equivalent. Immunogenicity study did not show any evidence of anti-bevacizumab antibodies in blood serum samples.
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Tange, Naoyuki, Fumihiko Hayakawa, Takahiko Yasuda, Hideyuki Yamamoto, Daiki Hirano, Shinobu Tsuzuki, and Hitoshi Kiyoi. "Staurosporine Induces Caspase-Dependent Proteolysis of MEF2D-Fusion Protein and Cell Death Selective to MEF2D-Fusion-Positive ALL Cells." Blood 134, Supplement_1 (November 13, 2019): 1349. http://dx.doi.org/10.1182/blood-2019-123602.
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MEF2D fusion (M-fusion) genes are newly discovered recurrent gene abnormalities that are detected in approximately 5% of acute lymphoblastic leukemia (ALL) cases. We previously found that the loss of the micro RNA target site in wild-type MEF2D gene by translocation led to strong expression of M-fusion protein in ALL cells by evasion from micro RNA and that M-fusion protein inhibited the transcriptional activity of PAX5, a B-cell differentiation regulator, in a dose-dependent manner. These findings prompted us to explore drugs that induced proteolysis of M-fusion protein as possible therapeutic agents for M-fusion-positive ALL. We developed a high-throughput screening system to find compounds that reduced protein expression level of MEF2D. The expression vector of the fusion protein of N-terminal half of MEF2D (MEF2D N) and luciferase (MEF2D N-Luc) was stably transfected to 293T cells (MEF2D N-Luc/293T). Stable transfectant of the expression vector of luciferase was also established (Luc/293T). We could easily measure protein expression level in these cells by luciferase assay. We screened 3766 compounds with known pharmaceutical activities with this system and selected staurosporine, a multi-kinase inhibitor, as a possible proteolysis-inducer of MEF2D. Staurosporine strongly reduced the luciferase value in MEF2D N-Luc/293T but not in Luc/293T (Figure 1A). Staurosporine induced proteolysis of MEF2D-HNRNPUL1 (M-H) and MEF2D-DAZAP1 (M-D) in M-fusion-positive ALL cell lines within 6 h. Proteolysis of M-fusion proteins were inhibited not by MG-132, a proteasome inhibitor, but by Z-VAD FMK, a caspase inhibitor, indicating that these proteolyses were caspase-dependent (Figure 1B). Consistent with this, Z-VAD-FMK blocked apoptosis by staurosporine in M-H positive ALL cell lines . We confirmed the cleavage of M-H by caspase 3 and caspase 7 in vitro and identified the cleavage site (Figure 1C). Furthermore, staurosporine demonstrated stronger cytotoxic effect on M-fusion-positive ALL cell lines than M-fusion-negative ones (Figure 1D). These results indicated that staurosporine induced apoptosis of M-fusion-positive ALL cells through caspase-dependent proteolysis of M-fusion protein at least in part. Luciferase-based proteolysis screening provided a novel strategy for the development of anti-cancer drugs. Figure legends Figure 1. A. Staurosporine strongly reduced the luciferase value in MEF2D N-Luc/293T but not in Luc/293T. MEF2D N-Luc/293T were treated with 3766 compounds (2uM each) for 24 h. Then luciferase assays were performed to estimate the amount of MEF2D N-Luc protein. Top 15 compounds which reduced the relative luciferase value were selected for the second screening where compounds were added to MEF2D N-Luc/293T and Luc/293T, then we estimated their effect on the expression of MEF2D N-Luc and luciferase. Results of the second screening were plotted on a scattergram, on which the relative luciferase value in Luc/293T and MEF2D N-Luc/293T were set on the Y-axis and X-axis, respectively. Relative luciferase values are relative values to those of control cells treated with vehicle (DMSO). Staurosporine and K252a, an analog of staurosporine, were selected as hit compounds which reduced MEF2D N-Luc but not luciferase. B. Staurosporine reduced the expression of M-H and M-D, which inhibited by Z-VAD FMK. M-H-positive ALL cell lines, Kasumi-7 and Kasumi-9 and a M-D-positive ALL cell line, TS-2 were treated with 1uM staurosporine, 20uM Z-VAD-FMK, or both for 6 h. Cells were lysed and subjected to immunoblotting with indicated antibodies. C. Caspase-3 and caspase-7 cleaved M-H in vitro. M-H and its mutants with aspartate substitutions at possible caspase cleavage sites were synthesized with [35S]-methionine-labeled in vitro translation and were incubated with purified caspase-3 or -7. Cleaved fragments were resolved on SDS-PAGE and visualized by autoradiography. Mutant 4 was resistant to the cleavage by both caspases. D. Staurosporine demonstrated stronger cytotoxic effect on M-fusion-positive ALL cell lines than M-fusion-negative ones. ALL cell lines were treated with staurosporine at the indicated doses for 24 h. Cell viabilities were measured using MTT assay. Figure 1 Disclosures Kiyoi: Takeda Pharmaceutical Co., Ltd.: Research Funding; Pfizer Japan Inc.: Honoraria; Astellas Pharma Inc.: Honoraria, Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; FUJIFILM Corporation: Research Funding; Eisai Co., Ltd.: Research Funding; Bristol-Myers Squibb: Research Funding; Daiichi Sankyo Co., Ltd: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co.,Ltd.: Research Funding; Perseus Proteomics Inc.: Research Funding.
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Chehrynets, A. I., and V. O. Krasinko. "MARKET ANALYSIS OF IMMUNOBIOLOGICAL VETERINARY PREPARATIONS IN UKRAINE AND THE EFFICACY OF INACTIVATED VACCINES AGAINST NEWCASTLE DISEASE." Scientific and Technical Bulletin оf State Scientific Research Control Institute of Veterinary Medical Products and Fodder Additives аnd Institute of Animal Biology 22, no. 2 (October 7, 2021): 395–401. http://dx.doi.org/10.36359/scivp.2021-22-2.47.
Full textAbstract:
The article presents a range analysis of the registered immunobiological preparations on
Ukrainian market with a emphasis on inactivated vaccines against Newcastle Disease in poultry, as well as the results of comparative immunogenic efficacy evaluation of inactivated vaccines of domestic manufacturer Biotestlab Ltd and products of importer manufacturer.
According to the List of Veterinary Immunobiological Preparations, 594 veterinary immunobiological preparations are registered in Ukraine as at October 5, 2020 where 84 of them are live and inactivated vaccines against Newcastle Disease in poultry. These vaccines are mono- and polyvalent and represent 14.1 % of the total number of immunobiological preparations. Inactivated vaccines against Newcastle disease are represented by 35 preparations, which is 5.9 % of total quantity and where 23 % are monovalent and 77 % are polyvalent - in which a component against Newcastle disease are one of the valent.
According to the results of comparative studies of mono- and polyvalent vaccines against Newcastle disease of domestic manufacturer «Biotestlab» Ltd and vaccines of the importers was found that all studied drugs are immunogenic and provide protection of poultry sector against Newcastle disease.
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Yang, Na, Wei Deng, Qiaoling Sun, Junqing Liang, Linfang Wang, Shiming Fan, Renxiang Tang, et al. "HMPL-523, a Novel SYK Inhibitor Showed Anti-Tumor Activities In Vitro and In Vivo." Blood 128, no. 22 (December 2, 2016): 3970. http://dx.doi.org/10.1182/blood.v128.22.3970.3970.
Full textAbstract:
Abstract Introduction: Spleen Tyrosine Kinase (SYK), a non-receptor type of tyrosine kinase, is a member of Syk/ZAP70 tyrosine kinase family. It plays a pivotal role in the regulation of B-cell receptor (BCR) signal pathway, which regulates proliferation, differentiation and survival of B lymphocytes. The abnormal activation of BCR singling is closely related to transformation and development of B cell lymphoma. Targeting BCR downstream molecules, such as Bruton' tyrosine kinase (BTK) and phosphoinositide-3-kinase δ (PI3Kδ) has emerged as new therapeutic approaches and inhibitors of BTK and PI3Kδ were approved recently by FDA for treatment of some subtypes of B-cell malignancies. Currently, a couple small molecular inhibitors against SYK, another BCR downstream molecule, are under the early clinical development and showed initial efficacy in B cell lymphomas. HMPL-523, discovered and currently being developed in Phase I clinical trial by Hutchison MediPharma, is a novel, highly potent and selective SYK inhibitor (IC50: 0.025 μM). The anti-tumor activity of HMPL-523 was evaluated in this study. Methods: Inhibitory effects of HMPL-523 on cell viability were investigated in a panel of B cell lymphoma cell lines with SYK/BCR dysregulation by CellTiter-Glo luminescent or CCK-8 assay. The effect of HMPL-523 on SYK signaling pathway was detected by western blot. Annexin-V- positive and PI-negative population was recognized as apoptotic cells by FACS. Nude mice bearing B cell lymphoma xenograft tumors with SYK/BCR dysregulation were used to determine anti-tumor activity of HMPL-523 in vivo. Result: HMPL-523 blocked phosphorylation of BLNK, downstream protein of Syk, in human mantle cell line REC-1 and human plasma cell line ARH-7777 with IC50 of 0.105 µM and 0.173 μM, respectively. HMPL-523 also inhibited cell viability of Ba/F3 Tel-Syk with IC50 of 0.033 μM. Furthermore, inhibitory effects of HMPL-523 on cell viability were evaluated in a panel of B -cell lymphoma cell lines with SYK/BCR deregulation. Results showed that HMPL- 523 potently inhibited cell survival with IC50s from 0.4 to 2 μM. Consistent with the effect on cell viability, HMPL-523 increased the apoptotic rate of REC-1 cells. Moreover, HMPL-523 showed the synergistic activities on killing human diffused large B cell lymphoma (DLBCL) in combination with other drugs such as BTK inhibitor, PI3Kδ inhibitors and Bcl2 family inhibitor. The detailed mechanisms underlying the synergism are still under investigation. Anti-tumor activity of HMPL-523 was determined in Syk dependent xenograft models. Daily oral administration of 100 mg/kg HMPL-523 showed potent anti-tumor activity in B cell lymphoma REC-1 (TGI: 59%). Conclusion:HMPL-523 is a highly potent SYK inhibitor with good activity against B-cell lymphoma in pre-clinical in vitro and in vivo models, supporting further clinical research for HMPL-523 as either single agent or combination drug with other agents to treat B-cell malignancies e.g. DLBCL Disclosures Yang: Hutchison MediPharma Ltd: Employment, Research Funding. Deng:Hutchison MediPharma Ltd: Employment, Research Funding. Sun:Hutchison MediPharma Ltd: Employment, Research Funding. Liang:Hutchison MediPharma Ltd: Employment, Research Funding. Wang:Hutchison MediPharma Ltd: Employment, Research Funding. Fan:Hutchison MediPharma Ltd: Employment, Research Funding. Tang:Hutchison MediPharma Ltd: Employment, Research Funding. Yu:Hutchison MediPharma Ltd: Employment, Research Funding. Sun:Hutchison MediPharma Ltd: Employment, Equity Ownership. Zhou:Hutchison MediPharma Ltd: Employment, Research Funding. Dai:Hutchison MediPharma Ltd: Employment, Research Funding. Qing:Hutchison MediPharma Ltd: Employment, Research Funding. Su:Hutchison MediPharma Ltd: Employment, Research Funding. Ren:Hutchison MediPharma Ltd: Employment, Research Funding.
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Aksenova, M. S., E. N. Bocharova, S. G. Abbasova, A. S. Ponomarev, V. V. Loginova, M. V. Bolotnikova, N. V. Belskaya, et al. "Comparability of the Reference Drug Pulmozim and a Similar Drug Tigerase in Terms of their Pharmacodynamic, Toxicological and Pharmacokinetic Properties." Journal Biomed 19, no. 1 (April 7, 2023): 47–60. http://dx.doi.org/10.33647/2074-5982-19-1-47-60.
Full textAbstract:
This work presents research studies into the comparability of Tigerase® (inhalation solution, manufactured by JSC «GENERIUM», Russia) to the reference drug Pulmozim® (inhalation solution, manufactured by Hoffmann-La Roche Ltd., Switzerland). Both drugs contain human recombinant deoxyribonuclease I – dornase alpha as an active substance and are intended for the treatment of cystic fibrosis with pulmonary manifestations (cystic fibrosis). The specific enzymatic activity of dornase alpha was studied in vitro and ex vivo using samples of patients’ purulent sputum. The pharmacokinetic parameters of the drugs were studied in the blood serum, bronchi and lungs. The main physiological parameters (body weight and temperature, the state of the cardiovascular, respiratory, excretory systems, hematological and biochemical blood parameters, pathomorphological changes in the internal organs, including the state of the cornea of the eyes, mortality rates) were assessed in comparative studies of subchronic toxicity in juvenile and sexually mature rats using 28-day inhalation in doses of 0.2 mg/kg to sexually mature and 0.26 mg/kg to juvenile animals (the dose was 6 times higher than the recommended dose for clinical use). It was concluded that the drugs were comparable in terms of their enzymatic, mucolytic (secretolytic) DNase activity, safety profile, and basic pharmacokinetic parameters.
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Yates, Rowdy. "Living with Drugs (7th edition) by Michael Gossop Ashgate Publishing Ltd, London, UK, 2013, 292 pp, ISBN: 978-1-4094-4349-0." Addiction 108, no. 11 (August 14, 2013): 2031. http://dx.doi.org/10.1111/add.12288.
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Bose, D. "Cardiac excitation–contraction coupling: new developments." Canadian Journal of Physiology and Pharmacology 66, no. 9 (September 1, 1988): 1217. http://dx.doi.org/10.1139/y88-200.
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Over 100 years have elapsed since Sidney Ringer made the serendipitous discovery that calcium played a crucial role in amphibian cardiac contraction. Since then we have learned that this ion is an obligatory requirement for cardiac muscle of all species, and that the regulation of intracellular calcium levels is considerably more complex in the mammalian heart than previously thought. Part of this complexity is due to the involved design requirements of mammalian physiological processes. Another element of complexity is introduced by the quantitative differences in the involvement of various regulatory processes in different species. Finally, many significant technological advances in methods for investigating cardiac cellular functions have provided exciting experimental data. However, these data must be integrated into a unifying framework of knowledge of cardiac functions. Among the exciting recent developments are the use of a patch clamp technique to discover different kinds of calcium channels, a highly refined skinned fiber technique to study calcium-induced calcium release, and calcium indicator dyes and laser diffraction and scattering techniques to study the dynamics of calcium handling by the cell. These studies have not only provided clues about the normal functioning of the myocardial cell but have also reinforced the notion that altered function of the sarcoplasmic reticulum during intracellular calcium overload can influence sarcolemmal electrical function.This symposium, organized by the Pharmacological Society of Canada, examined some of the more recent technological advances in the field to provide a glimpse not only of the "state of the art" but also of future directions.This symposium was made possible by generous financial assistance from Boehringer Ingelheim (Canada) Ltd., Bristol-Myers Pharmaceutical Group, Canadian and Manitoba Heart Foundations, Ciba-Geigy Canada Ltd., Du Pont Canada Inc., Hoffmann LaRoche Ltd., Merck-Frosst Canada Inc., Miles Laboratories Inc., Nordic Laboratories Inc., Pfizer (Canada) Inc., Rhône-Poulenc Pharmaceuticals Inc., G. D. Searle of Canada, Ltd., Squibb Canada Inc., Sterling Drugs Ltd./Winthrop Laboratories, the Upjohn Company of Canada, and the University of Manitoba Pharmacology Department.
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Aoki, Tomohiro, Kazuyuki Shimada, Akihiko Sakamoto, Keiki Sugimoto, Takanobu Morishita, Yuki Kojima, Satoko Shimada, et al. "Emetine Elicits Apoptosis of Intractable B-Cell Lymphoma Cells with MYC Rearrangement through Inhibition of Glycolytic Metabolism." Blood 128, no. 22 (December 2, 2016): 3019. http://dx.doi.org/10.1182/blood.v128.22.3019.3019.
Full textAbstract:
Abstract Background: Despite remarkable advances of initial treatment in diffuse large B-cell lymphoma (DLBCL), the prognosis of the disease with MYC rearrangement remains poor with a median overall survival of less than 1 year. The application of intensive or targeting treatment failed to show a benefit for the disease, an innovative approach should be thus required to overcome the obstacle of MYC rearrangement. Recent findings revealed that the close interaction of tumor cells with stromal cells in its microenvironment is involved in resistance to chemotherapy, and that tumor microenvironment has been shed light on a potential attractive therapeutic target. Purpose: To overcome poor prognoses of intractable DLBCL with MYC rearrangement, we explored an effective drug targeting tumor microenvironment through the high-throughput drug screening (Sugimoto et al. Sci Rep. 2015). Material and methods: Allpatient samples were experimentally used with written informed consent. To perform drug screening against primary patient lymphoma cells with intractable clinical course,we firstly developed co-culture system of lymphoma cells and stromal cells, which allowed us to culture them in vitro.For this, isolated stromal cells derived from human lymph node were prepared. Then 3,440 compounds mainly containing known pharmacologically active substance or off-patent drugs were screened to identify effective drugs for patient lymphoma cells. The efficacy and mechanism of action of the drug were confirmed by subsequent in vitro and in vivo analyses. Results: Two patient tumor cells with MYC/BCL2 rearrangement were used for the drug screening. Both patients developed refractory diseases within 1 year after diagnosis. In the screening analyses, primary lymphoma cells obtained from lymph node for patient (Pt) #1 were used, and tumor cells from PDX mouse model for Pt #2 were used to validate the result of Pt #1. The both tumor cells could not survive in in vitro monoculture, while the both lymphoma cells could remarkably survive longer in co-culture with stromal cells. Then we performed drug screening against primary tumor cells from Pt #1. Ninety-nine compounds with the viability of tumor cells less than 0.5 were identified, and we validated cell death of these 99 compounds against the other lymphoma cells from Pt #2. Among 10 compounds identified as potentially effective for the both tumor cells, we picked out emetine, which induced cell death against the both cells with an IC50 of 312 nM and 506 nM, respectively. Regarding the effect of emetine on stromal cells, the proliferation and survival was not affected in the concentration of 2 µM emetine whose concentration was used for the screening. However, stromal cells pretreated 0.5 µM emetine decreased a support potential to tumor cells resulting from decreased ATP production and glutathione in tumor cells. In terms of the effect of emetine on tumor cells, the drug induced a G2/M arrest in tumor cells, which resulted in induction of apoptosis. Based on previous finding that emetine suppresses HIF-1a expression, which is one of key regulators glucose metabolisms, we investigated the expression in tumor cells under the treatment of emetine. HIF-1a expression was suppressed in tumor cells as expected; we subsequently analyzed the status of glucose metabolism in tumor cells. The expression of key enzymes including HK2, PDK1, and LDHA were suppressed and ATP production and GLUT1 expression were also suppressed. The serial cascade of the alteration of glucose metabolism including the decreased mitochondrial membrane potential, the alteration of pentose phosphate pathway, and the reduction of NADPH and glutathione leading to the accrual of reactive oxygen species (ROS) was observed under the presence of emetine. In in vivo analyses, significant growth inhibition was observed under the emetine treatment (Figure A and B). Conclusions: Emetine identified by the drug screening is clearly effective for patient lymphoma cells with intractable clinical course in vitro and in vivo. Subsequent analyses regarding the mechanism of action of emetine revealed that the drug affected the both tumor cells and stromal cells in tumor microenvironment through the inhibition of glucose metabolism. Further investigations of the translation to clinic should be warranted. Disclosures Sugimoto: Otsuka Pharmaceutical Co., Ltd.: Employment. Kiyoi:Nippon Shinyaku Co., Ltd.: Research Funding; Fujifilm Corporation: Patents & Royalties, Research Funding; Eisai Co., Ltd.: Research Funding; Astellas Pharma Inc.: Consultancy, Research Funding; Phizer Japan Inc.: Research Funding; Yakult Honsha Co.,Ltd.: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding; MSD K.K.: Research Funding; Alexion Pharmaceuticals: Research Funding; Novartis Pharma K.K.: Research Funding; Mochida Pharmaceutical Co., Ltd.: Research Funding; Toyama Chemikal Co.,Ltd.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; AlexionpharmaLLC.: Research Funding; JCR Pharmaceutlcals Co.,Ltd.: Research Funding; Nippon Boehringer Ingelheim Co., Ltd.: Research Funding; Celgene Corporation: Consultancy; Zenyaku Kogyo Co.LTD.: Research Funding; Kyowa-Hakko Kirin Co.LTD.: Research Funding; Chugai Pharmaceutical Co. LTD.: Research Funding.
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Nakamura, Ayano, Susumu Suzuki, Masao Seto, Souichi Takasugi, Jo Kanasugi, Ichiro Hanamura, Ryuzo Ueda, and Akiyoshi Takami. "Synergistic Effect of Venetoclax for Antibody Dependent Cell Cytotoxicity By Daratumumab." Blood 136, Supplement 1 (November 5, 2020): 8–9. http://dx.doi.org/10.1182/blood-2020-134486.
Full textAbstract:
The prognosis of multiple myeloma (MM) has improved following the development of new drugs such as proteasome inhibitors and immunomodulatory drugs, but many patients are refractory to existing therapy. Venetoclax is a selective, orally bioavailable inhibitor of BCL2, showing efficacy in not only the monotherapy but also as the combination therapy of MM patients, especially those harboring t (11;14). Herein, we aimed to evaluate the synergistic cytotoxicity of venetoclax and daratumumab in vitro using KMS12PE and SKMM1 cell lines. The cells were treated with venetoclax and daratumumab targeting BCL2 and CD38, respectively. Flow cytometry showed that both cells were good therapeutic targets for daratumumab with the positive ratio of CD38 being 100% and 75.7% in KMS12PE and SKMM1, respectively (Figure 1). Western blotting showed that BCL2 expression was strongly detected in KMS12PE but barely in SKMM1 cells (Figure 2). Furthermore, using the WST1 assay for evaluating the cytotoxicity of venetoclax, we observed that KMS12PE cells were sensitive to 100 nM of venetoclax while SKMM1 cells were not sensitive up to 10 uM, which corresponded with the expression levels of BCL2 in both the cells (Figure 3). Then, the cytotoxicities of venetoclax, daratumumab, and their combination, were compared using flow cytometry with annexin V detection; the results indicated that the combination therapy exhibited higher cytotoxicity than the monotherapies. This experiment was repeated 3 times, and the average value with standard deviation (SD) is shown in Figure 4. Collectively, these results indicate that the antibody-dependent cell-mediated cytotoxicity was enhanced in KMS12PE cells harboring t (11;14) with high BCL2 expression, suggesting that the combination of venetoclax and daratumumab displays a synergistic effect in treating MM harboring t (11;14) with high BCL2 expression. Our data support the results of a recent phase І/II clinical trial for MM (Bahlis N et al. Blood 2019;925-925.), wherein 24 patients with R/R MM were treated with a combination therapy of venetoclax, daratumumab and dexamethasone, and the efficacy and safety of the therapy were evaluated. The ORR of the patients with t (11;14) treated with the combination therapy was 92%, which demonstrated the significant efficacy of the combination treatment. Thus, while the efficacy of the combination therapy of venetoclax and daratumumab has already been confirmed in a clinical trial, our data further shows the synergistic cytotoxic effect of venetoclax and daratumumab in vitro. Our in vitro analysis could, therefore, serve useful in the estimation of the effective dosage of each drug for the treatment of MM using clinical samples. Disclosures Hanamura: DAIICHI SANKYO COMPANY, LIMITED: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ono Pharmaceutical Co., Ltd.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen Pharmaceutical K.K.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi K.K.: Research Funding; Takeda Pharmaceutical Company Limited: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kyowa Kirin Co., Ltd.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eisai Co., Ltd.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; NIPPON SHINYAKU CO.,LTD.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer Japan Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Otsuka Pharmaceutical Co., Ltd.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SHIONOGI Co., Ltd.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Mundipharma K.K.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD K.K.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis Pharma K.K.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Ueda:Chugai Pharmaceutical Co., Ltd.: Research Funding; Kyowa Kirin Co., Ltd.: Research Funding; Ono Pharmaceutical Co., Ltd.: Research Funding. Takami:Yamada Bee Farm: Research Funding; Fukuyuukai: Research Funding; Novartis Pharma K.K.: Honoraria; Kyowa Kirin Co., Ltd.: Research Funding; Pfizer Japan Inc.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Astellas Pharma Inc.: Research Funding. OffLabel Disclosure: The combination therapy of daratumumab with venetoclax for multiple myeloma.